Hubbry Logo
CDKN1BCDKN1BMain
Open search
CDKN1B
Community hub
CDKN1B
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
CDKN1B
CDKN1B
CDKN1B
View on Wikipedia
from Wikipedia

CDKN1B
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCDKN1B, CDKN4, KIP1, MEN1B, MEN4, P27KIP1, cyclin-dependent kinase inhibitor 1B, cyclin dependent kinase inhibitor 1B
External IDsOMIM: 600778; MGI: 104565; HomoloGene: 2999; GeneCards: CDKN1B; OMA:CDKN1B - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1027

12576

Ensembl

ENSG00000111276

ENSMUSG00000003031

UniProt

P46527

P46414

RefSeq (mRNA)

NM_004064

NM_009875

RefSeq (protein)

NP_004055

NP_034005

Location (UCSC)Chr 12: 12.69 – 12.72 MbChr 6: 134.9 – 134.9 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene.[5] It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. It is often referred to as a cell cycle inhibitor protein because its major function is to stop or slow down the cell division cycle.

Function

[edit]

The p27Kip1 gene has a DNA sequence similar to other members of the "Cip/Kip" family which include the p21Cip1/Waf1 and p57Kip2 genes. In addition to this structural similarity the "Cip/Kip" proteins share the functional characteristic of being able to bind several different classes of Cyclin and Cdk molecules. For example, p27Kip1 binds to cyclin D either alone, or when complexed to its catalytic subunit CDK4. In doing so p27Kip1 inhibits the catalytic activity of Cdk4, which means that it prevents Cdk4 from adding phosphate residues to its principal substrate, the retinoblastoma (pRb) protein. Increased levels of the p27Kip1 protein typically cause cells to arrest in the G1 phase of the cell cycle. Likewise, p27Kip1 is able to bind other Cdk proteins when complexed to cyclin subunits such as Cyclin E/Cdk2 and Cyclin A/Cdk2.[6]

Regulation

[edit]

In general, extracellular growth factors which promote cell division reduce transcription and translation of p27Kip1. Also, increased synthesis of CDk4,6/cyclin D causes binding of p27 to this complex, sequestering it from binding to the CDk2/cyclin E complex. Furthermore, an active CDK2/cyclin E complex will phosphorylate p27 and tag p27 for ubiquitination.[7] A mutation of this gene may lead to loss of control over the cell cycle leading to uncontrolled cellular proliferation.[8][9][10] Loss of p27 expression has been observed in metastatic canine mammary carcinomas.[11][12][13] Decreased TGF-beta signalling has been suggested to cause loss of p27 expression in this tumor type.[14]

A structured cis-regulatory element has been found in the 5' UTR of the P27 mRNA where it is thought to regulate translation relative to cell cycle progression.[15]

P27 regulation is accomplished by two different mechanisms. In the first its concentration is changed by the individual rates of transcription, translation, and proteolysis. P27 can also be regulated by changing its subcellular location [16] Both mechanisms act to reduce levels of p27, allowing for the activation of Cdk1 and Cdk2, and for the cell to begin progressing through the cell cycle.

Transcription

[edit]

Transcription of the CDKN1B gene is activated by Forkhead box class O family (FoxO) proteins which also acts downstream to promote p27 nuclear localization and decrease levels of COP9 subunit 5(COPS5) which helps in the degradation of p27.[17] Transcription for p27 is activated by FoxO in response to cytokines, promyelocytic leukaemia proteins, and nuclear Akt signaling.[17] P27 transcription has also been linked to another tumor suppressor gene, MEN1, in pancreatic islet cells where it promotes CDKN1B expression.[17]

Translation

[edit]

Translation of CDKN1B reaches its maximum during quiescence and early G1.[17] Translation is regulated by polypyrimidine tract-binding protein(PTB), ELAVL1, ELAVL4, and microRNAs.[17] PTB acts by binding CDKN1b IRES to increase translation and when PTB levels decrease, G1 phase is shortened.[17] ELAVL1 and ELAVL4 also bind to CDKN1B IRES but they do so in order to decrease translation and so depletion of either results in G1 arrest.[17]

Proteolysis

[edit]

Degradation of the p27 protein occurs as cells exit quiescence and enter G1.[17] Protein levels continue to fall rapidly as the cell continues through G1 and enters S phase. One of the most understood mechanisms for p27 proteolysis is the polyubiquitylation of p27 by the SCFSKP2 kinase associated protein 1 (Skp1) and 2 (Skp2).[17] SKP1 and Skp2 degrades p27 after it has been phosphorylated at threonine 187 (Thr187) by either activating cyclin E- or cyclin A-CDK2. Skp2 is mainly responsible for the degradation of p27 levels that continues through S phase.[18] However it is rarely expressed in early G1 where p27 levels first begin to decrease. During early G1 proteolysis of p27 is regulated by KIP1 Ubiquitylation Promoting Complex (KPC) which binds to its CDK inhibitory domain.[19] P27 also has three Cdk-inhibited tyrosines at residues 74, 88, and 89.[17] Of these, Tyr74 is of special interest because it is specific to p27-type inhibitors.[17]

Nuclear export

[edit]

Alternatively to the transcription, translation, and proteolytic method of regulation, p27 levels can also be changed by exporting p27 to the cytoplasm. This occurs when p27 is phosphorylated on Ser(10) which allows for CRM1, a nuclear export carrier protein, to bind to and remove p27 from the nucleus.[20] Once p27 is excluded from the nucleus it cannot inhibit the cell's growth. In the cytoplasm it may be degraded entirely or retained.[16] This step occurs very early when the cell is exiting the quiescent phase and thus is independent of Skp2 degradation of p27.[20]

MicroRNA regulation

[edit]

Because p27 levels can be moderated at the translational level, it has been proposed that p27 may be regulated by miRNAs. Recent research has suggested that both miR-221 and miR-222 control p27 levels although the pathways are not well understood.[16]

Role in cancer

[edit]

Proliferation

[edit]

p27 is considered a tumor suppressor because of its function as a regulator of the cell cycle.[17] In cancers it is often inactivated via impaired synthesis, accelerated degradation, or mislocalization.[17] Inactivation of p27 is generally accomplished post-transcription by the oncogenic activation of various pathways including receptor tyrosine kinases (RTK), phosphatilidylinositol 3-kinase (PI3K), SRC, or Ras-mitogen activated protein kinase(MAPK).[17] These act to accelerate the proteolysis of the p27 protein and allow the cancer cell to undergo rapid division and uncontrolled proliferation.[17] When p27 is phosphorylated by Src at tyrosine 74 or 88 it ceases to inhibit cyclinE-cdk2.[21] Src was also shown to reduce the half life of p27 meaning it is degraded faster.[21] Many epithelial cancers are known to overexpress EGFR which plays a role in the proteolysis of p27 and in Ras-driven proteolysis.[17] Non-epithelial cancers use different pathways to inactivate p27.[17] Many cancer cells also upregulate Skp2 which is known to play an active role in the proteolysis of p27[18] As a result, Skp2 is inversely related to p27 levels and directly correlates with tumor grade in many malignancies.[18]

Metastasis

[edit]

In cancer cells, p27 can also be mislocalized to the cytoplasm in order to facilitate metastasis. The mechanisms by which it acts on motility differ between cancers. In hepatocellular carcinoma cells p27 co-localizes with actin fibers to act on GTPase Rac and induce cell migration.[22] In breast cancer cytoplasmic p27 reduced RHOA activity which increased a cell's propensity for motility.[23]

This role for p27 may indicate why cancer cells rarely fully inactivate or delete p27. By retaining p27 in some capacity it can be exported to the cytoplasm during tumorigenesis and manipulated to aid in metastasis. 70% of metastatic melanomas were shown to exhibit cytoplasmic p27, while in benign melanomas p27 remained localized to the nucleus.[24] P27 is misplaced to the cytoplasm by the MAP2K, Ras, and Akt pathways although the mechanisms are not entirely understood.[25][26][27] Additionally, phosphorylation of p27 at T198 by RSK1 has been shown to mislocalize p27 to the cytoplasm as well as inhibit the RhoA pathway.[28] Because inhibition of RhoA results in a decrease in both stress fibers and focal adhesion, cell motility is increased.[29] P27 can also be exported to the cytoplasm by oncogenic activation of the P13K pathway.[29] Thus, mislocalization of p27 to the cytoplasm in cancer cells allows them to proliferate unchecked and provides for increased motility.

In contrast to these results, p27 has also been shown to be an inhibitor of migration in sarcoma cells.[30] In these cells, p27 bound to stathmin which prevents stathmin from binding to tubulin and thus polymerization of microtubules increased and cell motility decreased.[30]

MicroRNA regulation

[edit]

Studies of various cell lines including glioblastoma cell lines, three prostate cancer cell lines, and a breast tumor cell line showed that suppressing miR-221 and miR-22 expression resulted in p27-dependent G1 growth arrest[16] Then when p27 was knocked down, cell growth resumed indicating a strong role for miRNA regulated p27.[16] Studies in patients have demonstrated an inverse correlation between miR-221&22 and p27 protein levels. Additionally nearby healthy tissue showed high expression of the p27 protein while miR-221&22 concentrations were low.[16]

Regulation in specific cancers

[edit]

In most cancers reduced levels of nuclear p27 are correlated with increased tumor size, increased tumor grade, and a higher propensity for metastasis. However the mechanisms by which levels of p27 are regulated vary between cancers.

Breast

[edit]

In breast cancer, Src activation has been shown to correlate with low levels of p27[21] Breast cancers that were Estrogen receptor negative and progesterone receptor negative were more likely to display low levels of p27 and more likely to have a high tumor grade.[21] Similarly, breast cancer patients with BRCA1/2 mutations were more likely to have low levels of p27.[31]

Prostate

[edit]

A mutation in the CDKN1B gene has been linked to an increased risk for hereditary prostate cancer in humans.[32]

Multiple Endocrine Neoplasia

[edit]

Mutations in the CDKN1B gene has been reported in families affected by the development of primary hyperparathyroidism and pituitary adenomas, and has been classified MEN4 (multiple endocrine neoplasia, type 4). Testing for CDKN1B mutations has been recommended in patients with suspected MEN, in whom previous testing for, the more common MEN1/RET mutation, is negative.[33]

Clinical significance

[edit]

Prognostic value

[edit]

Several studies have demonstrated that reduced p27 levels indicate a poorer patient prognosis.[17] However, because of the dual, contrasting roles p27 plays in cancer (as an inhibitor of growth and as a mechanism for metastasis) low levels of p27 may demonstrate that a cancer is not aggressive and will remain benign.[17] In ovarian cancer, p27 negative tumors progressed in 23 months compared to 85 months in p27 positive tumors and thus could be used as a prognostic marker.[34] Similar studies have correlated low levels of p27 with a worse prognosis in breast cancer.[35] Colorectal carcinomas that lacked p27 were shown to have increased p27-specific proteolysis and a median survival of only 69 months compared to 151 months for patients with high or normal levels of p27.[36] The authors proposed clinicians could use patient specific levels of p27 to determine who would benefit from adjuvant therapy.[36] Similar correlations were observed in patients with non-small cell lung cancer,[37] those with colon,[37] and prostate cancer.[38]

So far studies have only evaluated the prognostic value of p27 retrospectively and a standardized scoring system has not been established.[17] However it has been proposed that clinicians should evaluate a patient's p27 levels in order to determine if they will be responsive to certain chemotoxins which target fast growing tumors where p27 levels are low.[17] Or in contrast, if p27 levels are found to be high in a patient's cancer, their risk for metastasis is higher and the physician can make an informed decision about their treatment plan.[17] Because p27 levels are controlled post-transcriptionally, proteomic surveys can be used to establish and monitor a patient's individual levels which aids in the future of individualized medicine.

The following cancers have been demonstrated to have an inverse correlation with p27 expression and prognosis: oro-pharyngo-laryngeal, oesophageal, gastric, colon, lung, melanoma, glioma, breast cancer, prostate, lymphoma, leukemia.[18]

Correlation to treatment response

[edit]

P27 may also allow clinicians to better select an appropriate treatment for a patient. For example, patients with non-small cell lung cancer who were treated with platinum based chemotherapy showed reduced survival if they had low levels of p27.[39] Similarly low levels of p27 correlated with poor results from adjuvant chemotherapy in breast cancer patients.[40]

Value as a therapeutic target

[edit]

P27 has been explored as a potential target for cancer therapy because its levels are highly correlated to patient prognosis.[41] This is true for a wide spectrum of cancers including colon, breast, prostate, lung, liver, stomach, and bladder.[41]

Use of microRNAs for therapy

[edit]

Because of the role miRNAs play in p27 regulation, research is underway to determine if antagomiRs that block the activity of the miR221&222 and allow for p27 cell grow inhibition to take place could act as therapeutic cancer drugs.[16]

Role in Regeneration

[edit]

Knockdown of CDKN1B stimulates regeneration of cochlear hair cells in mice. Since CDKN1B prevents cells from entering the cell cycle, inhibition of the protein could cause re-entry and subsequent division. In mammals where regeneration of cochlear hair cells normally does not occur, this inhibition could help regrow damaged cells who are otherwise incapable of proliferation. In fact, when the CDKN1B gene is disrupted in adult mice, hair cells of the organ of Corti proliferate, while those in control mice do not. Lack of CDKN1B expression appears to release the hair cells from natural cell-cycle arrest.[42][43] Because hair cell death in the human cochlea is a major cause of hearing loss, the CDKN1B protein could be an important factor in the clinical treatment of deafness.

Interactions

[edit]

CDKN1B has been shown to interact with:

Overview of signal transduction pathways involved in apoptosis.

See also

[edit]

References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

CDKN1B

View on Grokipedia
from Grokipedia
CDKN1B is a protein-coding located on chromosome 12p13.1 that encodes inhibitor 1B, commonly known as p27Kip1, a key regulator of the that inhibits the activity of (CDK) complexes to prevent progression from the to the . This 198-amino-acid protein functions primarily by binding to and inhibiting E-CDK2 and D-CDK4/6 complexes, thereby maintaining cellular quiescence and responding to antiproliferative signals such as damage or differentiation cues. Beyond its core inhibitory role, p27Kip1 acts as a , facilitating the assembly of certain CDK complexes and modulating non-cell cycle processes including , , and through interactions with proteins like RhoA and c-Jun. The regulation of CDKN1B expression and p27Kip1 activity is tightly controlled at multiple levels to ensure precise control. Transcriptionally, the is responsive to growth factors and stress signals, while post-translationally, the protein undergoes (e.g., at Thr187 by CDK2 or Tyr88 by Src kinases) leading to ubiquitination and proteasomal degradation, which is essential for . Nuclear export via at Ser10 allows cytosolic localization, where p27Kip1 influences dynamics and cell motility. As an intrinsically disordered protein, p27Kip1 exhibits high conformational flexibility, enabling it to adopt structured conformations upon binding partners, which underlies its multifaceted roles. Dysregulation of CDKN1B is implicated in various pathologies, particularly as a tumor suppressor. heterozygous mutations, such as variants (e.g., W76X) or frameshifts, cause type 4 (MEN4), characterized by tumors in the pituitary, parathyroid, and other endocrine tissues. Somatic alterations, including low expression or inactivating mutations, are associated with aggressive cancers like , , colorectal, and neuroendocrine tumors, correlating with poor due to unchecked proliferation. Additionally, p27Kip1 promotes tumorigenesis in mouse models, highlighting its role in suppressing and maintaining tissue homeostasis.

Gene and Protein Overview

Gene Structure and Expression

The CDKN1B gene is situated on the short arm of human chromosome 12 at locus 12p13.1, spanning approximately 37 kilobases of genomic DNA from position 12,685,498 to 12,722,373 on the forward strand (GRCh38 assembly). This genomic region encompasses three exons, with the coding sequence distributed across exons 2 and 3, while exon 1 is primarily non-coding and includes part of the 5' untranslated region. The gene's compact structure facilitates tight transcriptional control, essential for its role in cell cycle regulation. The promoter of CDKN1B lacks a , characteristic of many and cell cycle-related genes, relying instead on initiator elements and proximal binding sites for basal transcription. Key regulatory features include consensus binding sites for Forkhead box O (FoxO) transcription factors, such as FoxO1, located upstream of the transcription start site. These sites enable FoxO-mediated activation in response to signaling or stress conditions, promoting CDKN1B transcription in nutrient-deprived or growth-arrested states. CDKN1B demonstrates ubiquitous basal expression across human tissues, as detected by and analyses, reflecting its fundamental role in cellular . According to GTEx data (as of 2023), expression levels vary, with the highest median TPM observed in (~35-40 TPM), high levels in heart and (~25 TPM), moderate levels in liver (~15 TPM) and colon (~12 TPM), where it supports maintenance of the G0/G1 phase in non-proliferating cells; in contrast, lower expression occurs in rapidly dividing tissues like and testis (~5-10 TPM). These patterns align with CDKN1B's upregulation in response to antiproliferative signals, contributing to restraint in post-mitotic environments. Older studies reported highest levels in , but provides a more comprehensive view. Alternative splicing of CDKN1B pre-mRNA generates at least 10 transcript variants, though the majority are lowly expressed and predicted to produce non-coding or truncated products. The canonical isoform, encoded by transcript ENST00000228872 (NM_004064.5), translates to the full-length p27Kip1 protein of 198 , which predominates in most tissues. Rare isoforms, such as those retaining intronic sequences or altering the 3' , may modulate mRNA stability or localization but lack well-characterized functional impacts.

Protein Structure and Localization

The p27Kip1 protein, encoded by the CDKN1B gene, consists of 198 with a calculated molecular weight of approximately 22 kDa, though post-translational modifications such as can increase its apparent size to around 27 kDa on SDS-PAGE gels. The protein features an intrinsically disordered structure, particularly in its N- and C-terminal regions, which enables flexible interactions with binding partners. The N-terminal region contains the cyclin-binding domain spanning residues 1-65, which facilitates association with subunits in cyclin-CDK complexes. Adjacent to this is the central CDK-inhibitory domain (residues 28-106), also known as the kinase inhibitory domain (KID), which directly blocks the of cyclin-dependent kinases (CDKs) to inhibit their activity. The C-terminal region harbors a nuclear localization signal (NLS) at residues 153-187, promoting import into the nucleus, as well as a nuclear export signal () that mediates shuttling out of the nucleus. Key sites, such as 187 (Thr187), are targeted by CDK2, altering the protein's conformation and influencing both its stability and subcellular distribution by facilitating recognition for ubiquitin-mediated processes. Other sites, including serine 10 (Ser10) and 157 (Thr157), modulate localization through interactions with export machinery or retention factors like 14-3-3 proteins. p27Kip1 is predominantly localized in the nucleus during the G0 and G1 phases of the , where it exerts its inhibitory effects on progression. In response to mitogenic signals, events trigger its export to the via the CRM1-dependent pathway, utilizing the NES, which sequesters the protein away from nuclear CDK targets and potentially enables cytoplasmic functions.

Molecular Function

Cell Cycle Inhibition Mechanism

The protein product of CDKN1B, known as p27Kip1, primarily enforces arrest at the G1/S checkpoint by binding to and inhibiting cyclin E-CDK2 and cyclin A-CDK2 complexes. These inhibitory interactions prevent the phosphorylation of the (Rb), thereby maintaining Rb in its hypophosphorylated state and repressing the transcriptional activity of transcription factors essential for S-phase entry. In this manner, elevated p27Kip1 levels ensure that cells remain in G1 until growth-promoting signals are sufficient to titrate away the inhibitor. The inhibitory action of p27Kip1 follows a stoichiometric binding model, wherein a single p27Kip1 molecule associates with one CDK subunit within the cyclin-CDK complex. reveals that the of p27Kip1 inserts into the catalytic cleft of CDK2, directly occluding the ATP-binding site and distorting the kinase's active conformation to abolish phosphoryl transfer. This precise, one-to-one inhibition contrasts with non-stoichiometric models and underscores p27Kip1's efficiency as a tight-binding CDK regulator. In maintaining G0 quiescence, p27Kip1 additionally sequesters D-CDK4/6 complexes in an inactive state at high p27Kip1 concentrations typical of non-proliferating states, while at lower levels it promotes their assembly and nuclear localization. This sequestration mode involves p27Kip1, which initially promotes assembly of D-CDK4/6 but at excess levels binds and renders the holoenzymes inactive, reinforcing the quiescent phenotype by limiting early G1 progression. A key feedback mechanism amplifying p27Kip1-mediated involves its induction via the transforming growth factor-β (TGF-β) signaling pathway, which transcriptionally upregulates CDKN1B expression to enforce G1 in response to antiproliferative cues. This pathway links extracellular growth inhibitors to intracellular CDK suppression, ensuring rapid and sustained blockade.

Binding to Cyclin-CDK Complexes

p27Kip1, encoded by the CDKN1B gene, primarily exerts its inhibitory effects on progression by binding to (CDK) complexes, with a particular emphasis on interactions involving G1/S-phase regulators. The binding process is sequential, beginning with the recognition of the subunit, which positions the inhibitory domain of p27Kip1 for subsequent engagement with the CDK. This mechanism ensures specific and high-affinity association with active cyclin-CDK holoenzymes, preventing substrate access and ATP binding at the catalytic site. A key feature of this interaction involves hydrophobic contacts within the cyclin-binding groove. The N-terminal domain of p27Kip1 docks into a hydrophobic pocket on the surface, exemplified by interactions with residues in the α-helices of E, such as Leu258 and Phe256, which stabilize the complex through van der Waals forces and contribute to specificity for cyclins over others. This initial docking induces a conformational rearrangement in p27Kip1, transitioning its intrinsically disordered inhibitory domain into a structured form. Notably, a short 310- in the second subdomain of p27Kip1 (residues approximately 28–36) inserts directly into the ATP-binding cleft of CDK2, occluding the and mimicking the ring of ATP to block binding and phosphate transfer. This insertion distorts the CDK2 catalytic loop, rendering the inactive without altering its overall fold. The affinity of p27Kip1 for these complexes varies, reflecting functional nuances in control. It exhibits high affinity for E- and A-CDK2 complexes, enabling potent suppression of S-phase entry. In contrast, binding to D-CDK4/6 is weaker, allowing partial activity in early G1 while still permitting inhibition at elevated p27Kip1 levels. This differential affinity arises from subtle structural differences in the cyclin grooves and CDK activation loops, with E/A forming tighter interfaces via conserved motifs like the MRAIL in p27Kip1. p27Kip1 displays a biphasic role in modulating D-CDK4 assembly, dependent on its concentration. At low levels, p27Kip1 acts as a scaffold, promoting the formation and nuclear localization of active D-CDK4 complexes by stabilizing subunit interactions and facilitating T-loop , as evidenced in p27/p21 double-knockout fibroblasts where complex assembly is severely impaired. Recent structural studies have revealed that p27Kip1 allosterically activates CDK4 by rotating its T-loop, facilitating and activity in the D-CDK4-p27 ternary complex at low p27 levels. However, at higher concentrations, p27Kip1 shifts to a dominant inhibitory mode, fully blocking CDK4 activity by occupying the catalytic site and preventing substrate , thus enforcing G1 under stress or quiescence signals. This dual functionality fine-tunes G1 progression without overlapping the broader inhibitory effects on CDK2 complexes.

Regulation of Expression and Activity

Transcriptional Control

The transcriptional regulation of the CDKN1B gene, which encodes the inhibitor p27^Kip1, is governed by a network of transcription factors that respond to mitogenic and stress signals, as well as epigenetic modifications that modulate promoter accessibility. Key activators include members of the Forkhead box O (FoxO) family, such as FoxO3a, which bind to specific sites in the CDKN1B promoter to drive its expression. Inhibition of the PI3K/AKT pathway, often triggered by deprivation or therapeutic agents, dephosphorylates FoxO3a, allowing its nuclear translocation and subsequent enhancement of CDKN1B transcription, thereby promoting arrest. In contrast, repressors like c-Myc suppress CDKN1B transcription during proliferative states by binding to elements in the promoter or indirectly inhibiting FoxO3a activity, facilitating progression. Similarly, E2F1 can contribute to repression in certain contexts by interacting with promoter elements, often in coordination with other factors to downregulate CDKN1B during S-phase entry. These opposing regulatory mechanisms ensure tight control of p27^Kip1 levels in response to extracellular cues like serum availability. Epigenetic alterations further fine-tune CDKN1B expression. Histone acetylation, particularly at H3K9ac marks on the promoter, correlates with an open state and active transcription, often observed in quiescent or differentiated cells. Conversely, hypermethylation of CpG islands in the CDKN1B promoter leads to in various cancers, reducing p27^Kip1 levels and promoting uncontrolled proliferation. These modifications are dynamically influenced by environmental signals, such as contact inhibition, which can upregulate CDKN1B through .

Post-Translational Modifications and Degradation

The stability and activity of the p27Kip1 protein, encoded by CDKN1B, are primarily regulated through post-translational modifications that influence its degradation, localization, and interactions with (CDK) complexes. In proliferating cells, p27Kip1 exhibits a short of approximately 2-6 hours, which is extended in quiescent cells to maintain arrest. A key regulatory mechanism involves ubiquitination and proteasomal degradation mediated by the SCFSkp2 ubiquitin ligase complex, which targets p27Kip1 following at threonine 187 (Thr187). This , often catalyzed by E-CDK2, creates a binding site for the adaptor protein Skp2, facilitating polyubiquitination and subsequent degradation by the 26S , thereby allowing G1/S progression. at Thr187 is essential for this process, as mutants lacking this site resist SCFSkp2-dependent degradation. Phosphorylation at specific sites modulates p27Kip1 activity and localization. 88 (Tyr88) phosphorylation by kinases such as Src or JAK2 disrupts p27Kip1 binding to CDK2, impairing its inhibitory function and promoting progression; this modification also enhances ubiquitination and degradation. Similarly, serine 10 (Ser10) phosphorylation by AKT kinase promotes binding to 14-3-3 proteins, leading to cytoplasmic retention of p27Kip1 and sequestration from nuclear CDKs. Other modifications further fine-tune p27Kip1 stability and localization. of residues, such as at position 100, prevents ubiquitination and stabilizes the protein, counteracting degradation pathways and sustaining its tumor-suppressive role. Sumoylation, mediated by UBE2I/ machinery, enhances nuclear retention by inhibiting CRM1-dependent export, thereby preserving p27Kip1's nuclear CDK-inhibitory activity in response to signals like TGF-β. These modifications collectively ensure precise control of p27Kip1 levels and function across phases.

MicroRNA and Other Non-Coding RNA Regulation

MicroRNAs (miRNAs) play a critical role in post-transcriptional regulation of CDKN1B, primarily by binding to its 3' untranslated region (3'UTR) to suppress translation or induce mRNA degradation, thereby reducing p27^Kip1 protein levels and promoting cell cycle progression in various cancers. Among these, the miR-221/222 cluster is a well-established oncogenic regulator that directly targets the CDKN1B 3'UTR, leading to decreased p27^Kip1 expression. This mechanism contributes to uncontrolled proliferation in breast cancer, where miR-221/222 overexpression correlates with estrogen receptor signaling and enhanced tumor growth, as well as in thyroid papillary carcinomas, where elevated levels of these miRNAs are associated with aggressive disease phenotypes. Other miRNAs, such as miR-16 and miR-106b, further contribute to CDKN1B suppression by inhibiting its translation, often in a cancer-specific context. MiR-16, frequently downregulated in cells under certain conditions, targets cell cycle regulators including components that indirectly stabilize p27^Kip1, but its enforced expression can suppress proliferation by modulating pathways. MiR-106b, part of the miR-106b9325 cluster, directly binds the CDKN1B transcript to repress p27^Kip1 synthesis, facilitating in gastric cancer cells where cluster overexpression is common. In contrast, members of the let-7 family exhibit tumor-suppressive effects by enhancing CDKN1B mRNA stability through indirect mechanisms, such as repressing factors that promote p27^Kip1 degradation, thereby sustaining cell cycle arrest in and other epithelial cancers. Long non-coding RNAs (lncRNAs) modulate CDKN1B expression through competitive endogenous RNA (ceRNA) networks, often by sponging miRNAs that target p27^Kip1. lncRNA GAS5 sequesters miR-222, relieving repression on CDKN1B and elevating p27^Kip1 to suppress hepatic fibrogenesis and tumor growth. These interactions highlight lncRNAs as key mediators of miRNA availability for CDKN1B regulation. Circular RNAs (circRNAs), a class of stable non-coding RNAs, are emerging as regulators of CDKN1B via miRNA sequestration. CircRNAs such as circ-YAP1 sponge miR-367-5p to derepress CDKN1B , reducing gastric proliferation by increasing p27^Kip1 abundance. In , circCRKL similarly acts as a miR-196a-5p/b-5p decoy, enhancing p27^Kip1-mediated . These underscore the potential of circRNAs as therapeutic targets for restoring p27^Kip1 function in .

Role in Cancer Pathogenesis

Suppression of Cell Proliferation

CDKN1B, encoding the inhibitor p27Kip1, exerts a tumor-suppressive effect by restraining , primarily through regulation of the G1/S transition. In p27Kip1 models, ablation of the gene results in uncontrolled progression from G1 to , leading to multi-organ , including enlarged pituitary glands, adrenal medullas, and gonads, as well as increased body size due to enhanced cellular proliferation. This phenotype underscores p27Kip1's essential role in maintaining proliferative , with heterozygous mice also showing predisposition to pituitary adenomas, further highlighting dosage-dependent suppression of aberrant growth. An inverse correlation exists between p27Kip1 expression levels and tumor aggressiveness across various malignancies. High p27Kip1 expression is typically observed in benign tumors, such as nevi in , where it effectively curbs proliferation, whereas low or heterogeneous expression predominates in aggressive malignant tumors, correlating with poorer and increased proliferative activity. Beyond its canonical inhibition of cyclin-CDK complexes, p27Kip1 contributes to suppression of cell proliferation by promoting cellular senescence via the retinoblastoma (Rb) pathway. Accumulation of p27Kip1 is necessary for Rb-mediated induction of senescence, as its depletion abrogates Rb's ability to enforce cell cycle arrest and maintain a senescent state, thereby linking CDK-independent functions to long-term proliferative control. A 2023 pan-cancer demonstrated CDKN1B downregulation in multiple tumor types, with protein expression reduced in approximately 60% of cancers, fostering proliferation signatures and adverse clinical outcomes.

Influence on Tumor Metastasis

The localization of p27Kip1 (encoded by CDKN1B) within cancer cells critically influences tumor cell motility and invasion, with distinct roles for its cytoplasmic and nuclear forms. In the , p27Kip1 promotes independent of its canonical (CDK) inhibitory function by binding directly to RhoA, a that regulates dynamics. This interaction interferes with guanine nucleotide exchange factors (GEFs), preventing RhoA activation and GDP/GTP cycling, which paradoxically enhances migratory dynamics in tumor cells such as fibroblasts and lines. Studies in p27Kip1-null models demonstrate reduced motility upon loss of this cytoplasmic function, underscoring its pro-invasive role in tumor progression. Conversely, nuclear p27Kip1 acts as a transcriptional repressor that suppresses epithelial-mesenchymal transition (EMT), a key process enabling metastasis, by directly associating with the promoters of EMT-inducing transcription factors. Specifically, p27Kip1 binds to the Twist1 promoter in a p130/E2F4-dependent manner, repressing its transcription and preventing the downregulation of epithelial markers like E-cadherin. This mechanism also extends to inhibiting Snail expression through similar repressive complexes, thereby maintaining epithelial integrity and limiting invasive potential in contexts like embryonic stem cell differentiation and early tumor stages. Loss of nuclear p27Kip1 leads to Twist1 upregulation and EMT-like morphological changes, facilitating dissemination. Clinically, reduced nuclear p27Kip1 expression correlates with increased metastatic risk, particularly in , where low levels are inversely associated with involvement and poorer . Meta-analyses of patient cohorts confirm that diminished nuclear p27Kip1 independently predicts higher rates of nodal and reduced overall survival, highlighting its utility as a for aggressive disease. Recent investigations into circulating tumor cells (CTCs) reveal that p27Kip1 modulates their invasive potential by promoting a drug-tolerant persister state. In breast cancer CTC cultures exposed to mitotic inhibitors, elevated p27Kip1 restricts and endomitosis via signaling, enabling reversible quiescence that enhances survival and regrowth capacity post-therapy. This adaptation increases CTC and metastatic seeding potential, as evidenced by 2024–2025 studies showing p27Kip1-dependent in ≤4N states.

Dysregulation in Specific Cancer Types

In , particularly the luminal subtypes, CDKN1B mutations and reduced p27 expression contribute to disease progression. The V109G polymorphism has been identified in luminal breast tumors, where it impairs p27 protein stability and correlates with aggressive phenotypes. A 2025 analysis of luminal-type cohorts demonstrated that low CDKN1B expression is significantly associated with reduced metastasis-free survival, highlighting its role in sustaining uncontrolled proliferation in these hormone receptor-positive tumors. In , dysregulation of CDKN1B often involves post-translational mechanisms rather than frequent genetic alterations. Overexpression of the ubiquitin ligase Skp2 promotes ubiquitin-mediated degradation of p27, leading to diminished CDKN1B activity and enhanced progression in androgen-dependent and castration-resistant tumors. Promoter hypermethylation of CDKN1B has been observed infrequently, contributing to epigenetic in a subset of cases, though this mechanism is less prevalent compared to Skp2-driven proteolysis. Germline mutations in CDKN1B define multiple endocrine neoplasia type 4 (MEN4), a hereditary characterized by endocrine tumors including pituitary adenomas. Nonsense variants, which result in truncated p27 proteins lacking functional domains, disrupt cell cycle inhibition and predispose carriers to pituitary tumorigenesis. A 2025 characterization of CDKN1B variants in MEN4 patients revealed that these truncating mutations abolish p27's ability to bind cyclin-CDK complexes, thereby accelerating pituitary and tumor formation. Emerging evidence points to CDKN1B alterations in other malignancies, including lung cancer (SCLC). In SCLC, where RB1 and TP53 losses already compromise the G1/S checkpoint, concurrent CDKN1B dysregulation—often through reduced expression—further exacerbates defects, promoting rapid tumor growth. Pan-cancer analyses indicate that CDKN1B hypermutation rates are generally low (typically below 3-4%), with higher frequencies observed in uterine and neuroendocrine tumors, where frameshift and missense variants predominate.

Clinical and Therapeutic Implications

Prognostic and Diagnostic Value

CDKN1B, encoding the inhibitor p27Kip1, serves as a valuable for assessing cancer through immunohistochemical evaluation of protein expression. Low nuclear p27Kip1 expression is associated with poor in , correlating with aggressive disease and reduced survival. Similarly, in , low nuclear p27Kip1 expression correlates with shorter recurrence-free survival and increased risk of progression. These findings underscore the utility of standardized IHC scoring systems, where low nuclear expression often signals heightened tumor aggressiveness and poorer outcomes. At the transcriptional level, reduced CDKN1B mRNA expression in tumor tissues predicts adverse prognosis across multiple cancers, as evidenced by analyses of (TCGA) datasets. For instance, in cohorts from TCGA, low CDKN1B mRNA levels are linked to shorter overall survival, with hazard ratios (HR) typically ranging from 1.5 to 2.0 in multivariate models adjusting for age, stage, and subtype. This pattern holds in other solid tumors, where diminished CDKN1B transcripts associate with increased tumor burden and metastatic potential, highlighting its potential as a non-invasive prognostic indicator via RNA-based assays. In the context of hereditary syndromes, germline variants in CDKN1B are diagnostic hallmarks of type 4 (MEN4), a condition predisposing individuals to endocrine tumors such as pituitary adenomas and parathyroid carcinomas. Molecular for CDKN1B mutations, including sequencing of coding exons, is recommended for screening in patients with familial or sporadic endocrine neoplasms suggestive of MEN syndromes, enabling early detection and surveillance. Identification of pathogenic variants, such as frameshift or missense alterations, confirms MEN4 diagnosis and guides clinical management, distinguishing it from MEN1. Recent pan-cancer analyses using TCGA data have reinforced CDKN1B's role as an independent prognostic factor. A 2023 study across 40 cancer types found variable CDKN1B expression, with high levels correlating to favorable outcomes in entities like kidney renal clear cell carcinoma (KIRC) and cholangiocarcinoma (CHOL), emphasizing its broad applicability in risk stratification.

Association with Treatment Response

In hormone receptor-positive (HR+) , high levels of phosphorylated (specifically at tyrosine-88) correlate with enhanced responsiveness to CDK4/6 inhibitors such as . This phosphorylation status reduces CDK4 activity and stratifies sensitive tumors in explant cultures, where pY88-positive samples exhibit significant decreases in Ki-67-positive cells following treatment, unlike pY88-negative counterparts. Conversely, decreased total p27Kip1 levels in resistant cell lines, like palbociclib-resistant variants, are associated with upregulated CDK2 activity, underscoring p27Kip1's role in maintaining sensitivity through inhibition. Regarding mitotic inhibitors like , used in , low p27Kip1 expression promotes (≥8N DNA content) as an escape mechanism from mitotic arrest, potentially contributing to resistance by allowing through endomitosis, though this often leads to without regrowth in circulating tumor cells (CTCs). In contrast, high p27Kip1 stabilizes via AKT-mediated serine-10 , restricting and enabling a reversible drug-tolerant persister (DTP) state limited to ≤4N ploidy, which supports CTC regrowth post-treatment. Suppression of p27Kip1 in persister-proficient CTCs shifts them toward and abrogates recovery, highlighting its dual role in modulating mitotic escape pathways. In , restoration of p27Kip1 enhances the efficacy of (ADT) by mediating therapy-induced through the p27Kip1/CDK/pRb pathway, promoting G1/S arrest and inhibiting proliferation. ADT upregulates p27Kip1 expression, leading to in androgen-dependent cells like and LAPC-4, with over 80% exhibiting senescent markers after 10 days of treatment; high p27Kip1 levels, coupled with Skp2 downregulation, amplify this response and counteract progression in xenografts. This mechanism positions p27Kip1 restoration as a sensitizer to ADT, improving outcomes by enforcing permanent growth arrest. Recent studies (2024–2025) further elucidate CDKN1B's involvement in drug-tolerant persister states following mitotic drug exposure, particularly in CTCs. Stabilized p27Kip1 facilitates DTP emergence by preventing excessive , allowing reversible tolerance to without permanent resistance; this was observed in 12 of 18 patient-derived CTC cultures, where p27Kip1 knockdown increased lethality via unchecked endomitosis. These findings suggest targeting p27Kip1 stabilization could disrupt persister formation and improve outcomes.

Strategies for Therapeutic Targeting

One key strategy for therapeutic targeting of CDKN1B (encoding p27Kip1) involves stabilizing the protein to prevent its degradation, thereby enhancing its inhibitory function in s. Skp2, a component of the SCFSkp2 complex, promotes p27 ubiquitination and proteasomal degradation, and its inhibition has shown promise in preclinical models. For instance, the small-molecule inhibitor SZL-P1-41 disrupts the Skp2-Skp1 interaction, selectively suppressing SCFSkp2 activity without affecting other cullin-RING ligases, leading to p27 accumulation and reduced proliferation in various lines. This approach has demonstrated anti-tumor effects in xenograft models, including decreased tumor growth in by elevating p27 levels and inhibiting downstream activity. Gene therapy approaches using viral vectors to deliver CDKN1B have been explored in preclinical cancer models to restore p27 expression and suppress tumor progression. Adenoviral vectors expressing p27Kip1 (Ad-p27) have been shown to inhibit proliferation in cell lines by inducing G1 arrest and , with no significant toxicity to normal cells. In vivo studies using these vectors in subcutaneous tumor models further confirmed reduced tumor volume and increased p27 protein levels, highlighting the potential for targeted delivery to overcome p27 downregulation in aggressive malignancies. Modulating microRNA regulation of CDKN1B represents another targeted intervention, particularly through antagomirs that inhibit oncogenic miRNAs. In glioblastoma, miR-221/222 directly suppress p27 translation, contributing to uncontrolled proliferation; antagomirs against these miRNAs restore p27 expression, inducing and sensitizing cells to chemotherapy in preclinical models. This strategy has shown efficacy in reducing tumor growth in orthotopic glioblastoma xenografts by elevating intratumoral p27 levels and disrupting progression. Recent innovations as of 2025 focus on upstream pathway modulation to leverage CDKN1B in specific cancers. In small cell lung cancer (SCLC), which often exhibits G1-S checkpoint defects including low p27 activity due to high signaling, dual inhibitors of A and RxL motifs (e.g., CIRc series) selectively induce lethality in SCLC cells by disrupting A-1 interactions and other RxL bindings, leading to replication stress and in tumors with RB1/TP53 alterations. As of November 2025, a Phase 1 (NCT06577987) is evaluating CID-078, a related RxL motif inhibitor, in advanced solid tumors including SCLC. For (CTC) persisters, which survive through p27 stabilization via AKT at serine 10, modulation strategies aim to disrupt this process; preclinical data indicate that enhancing p27 function via stabilizers can influence persister , though suppression reduces CTC regrowth in patient-derived models post-mitotic inhibitor exposure.

Role in Tissue Regeneration

Mechanisms in Cellular Reprogramming

p27Kip1, the protein encoded by CDKN1B, plays a critical role in regulating cellular reprogramming by inhibiting (CDK2) activity, which prevents premature entry into the in progenitor cells. This inhibition maintains quiescence and ensures proper timing of progression during developmental and regenerative processes, such as in retinal histogenesis where p27Kip1 constrains excessive proliferation of retinal progenitors to support ordered differentiation. In the context of reprogramming, this mechanism helps preserve progenitor identity by blocking unscheduled that could disrupt cell fate decisions. In retinal repair, p27Kip1 contributes to the quiescence of , the primary glial cells in the , and works alongside p21Cip1 (encoded by CDKN1A) as part of the Cip/Kip family of CDK inhibitors to limit and proliferation following injury. In mammalian models, such as those involving N-methyl-N-nitrosourea (MNU)-induced photoreceptor loss, upregulation of p21Cip1 modulates proteins to facilitate limited , while in sodium iodate (NaIO3)-induced damage, downregulation of p27Kip1 via Notch signaling promotes re-entry into the and neuronal differentiation. This combined regulatory action underscores their shared function in balancing quiescence against regenerative potential in mammals, where robust reprogramming is restrained compared to lower vertebrates like . During liver regeneration, downregulation of p27Kip1 is essential for enabling proliferation after partial . Following , p27Kip1 levels decrease rapidly, allowing CDK activation and re-entry in quiescent hepatocytes to restore tissue mass. This transient suppression is mediated by factors such as microRNA-221, which inhibits p27Kip1 translation, thereby promoting S-phase progression and regenerative expansion without leading to uncontrolled growth. A recent study demonstrated that combining overexpression with p27Kip1 knockdown via (AAV) vectors induces robust proliferation of in uninjured mammalian retinas, mimicking regenerative observed in non-mammals. This approach resulted in approximately 45% of re-entering the , with self-limiting divisions and evidence of neurogenic potential in daughter cells, highlighting p27Kip1 as a key barrier to mammalian retinal regeneration.

Applications in Regenerative Medicine

In vitro studies on neonatal cardiomyocytes demonstrate that siRNA-mediated knockdown of p27Kip1, in combination with other CDK inhibitors like p21Cip1, induces re-entry and proliferation, suggesting potential for enhancing cardiac repair in models of myocardial without long-term adverse effects. This approach promotes the generation of new cardiomyocytes from resident cell populations, as demonstrated by enhanced BrdU incorporation and mitotic indices. Similarly, targeting p27Kip1 in adult cardiac stem cells via genetic knockdown augments their self-renewal and differentiation potential, contributing to better functional recovery in ischemic models. In neural regeneration, inhibition of p27Kip1 facilitates the proliferation of progenitor cells (OPCs), which is crucial for remyelination and repair in demyelinating injuries. Studies in lesion models reveal that reducing p27Kip1 levels through or genetic manipulation increases OPC recruitment to the injury site, boosting their proliferation and subsequent differentiation into mature . This modulation enhances the number of myelinating cells, as evidenced by greater NG2-positive OPC density and improved axonal remyelination in p27Kip1-deficient conditions compared to controls. Such strategies hold potential for treating conditions like , where OPC exhaustion limits endogenous repair. Restoring p27Kip1 expression in senescent tissues offers a means to rebalance quiescence in compartments affected by age-related diseases. In aged s, activation of the AMPK/p27Kip1 pathway via pharmacological or genetic means promotes while suppressing and markers, such as SA-β-gal activity and INK4a levels. This restoration maintains stem cell quiescence, preventing exhaustion and supporting tissue in models of . Overexpression of p27Kip1 in these contexts similarly shifts aged cells toward a reversible quiescent state, enhancing their regenerative potential without inducing permanent arrest. In auditory regeneration, inhibition of p27Kip1 promotes the proliferation and regeneration of cochlear in mammalian models. Auditory -specific deletion of p27Kip1 in postnatal mice enables supporting cells to re-enter the , generating new and preserving normal hearing function. This approach highlights p27Kip1 as a barrier to inner ear repair, with potential therapeutic applications for caused by damage.

Protein Interactions

Core Interacting Partners

CDKN1B, also known as p27Kip1, primarily interacts with (CDK) complexes through its N-terminal (KID), which encompasses distinct motifs for binding and CDKs. This domain includes an RxL motif (D1) for recognition, a hydrophobic α-helix (LH) for initial docking, and a β-hairpin/310-helix (D2) that inserts into the CDK to inhibit ATP binding and activity. Specifically, p27Kip1 binds E-CDK2 and A-CDK2 with high affinity, forming inhibitory complexes that block G1/S progression; the of p27Kip1/ A/CDK2 reveals p27Kip1 as an extended polypeptide spanning both subunits, with residues like Arg194 forming hydrogen bonds to Glu42 on CDK2 and Pro272 on A. In contrast, binding to (D1, D2, or D3)-CDK4/6 complexes can promote their assembly at low p27Kip1 levels while inhibiting at higher concentrations, with at Tyr74 reducing affinity and facilitating activation. p27Kip1 degradation is mediated by E3 ubiquitin ligases, including Skp2 (part of the SCFSkp2 complex) and the KPC complex (KPC1/KPC2). Skp2 recognizes p27Kip1 phosphorylated at Thr187 (primarily by E-CDK2), recruiting it for polyubiquitination and proteasomal degradation during ; this interaction requires the adaptor Cks1 and occurs in the nucleus. The KPC complex targets cytoplasmic p27Kip1 in early following nuclear export, ubiquitinating it independently of Thr187 phosphorylation but dependent on the cullin-RING architecture. Signaling kinases such as AKT and GSK3β regulate p27Kip1 stability and localization through at specific sites. AKT directly p27Kip1 at Thr157 (and to a lesser extent Thr198), impairing its nuclear import by promoting 14-3-3 binding and cytosolic sequestration, thereby reducing CDK inhibition. GSK3β p27Kip1 at sites including Ser160 and Ser161 (in a pathway often primed by prior AKT inhibition) and contributes to its inactivation or degradation in response to signaling. Additional core partners include JAB1 (CSN5), which binds the C-terminal domain of p27Kip1 to facilitate its CRM1-dependent nuclear export, exposing it to cytoplasmic degradation pathways, and stathmin (STMN1), which interacts with the cyclin-binding domain of p27Kip1 to inhibit stathmin's microtubule-depolymerizing activity, thereby stabilizing and modulating in non-proliferative contexts. Beyond CDK-related interactions, p27Kip1 engages with non-cell cycle proteins to influence migration and transcription. It binds RhoA via its N-terminal domain, sequestering it from its effectors and inhibiting actomyosin contractility to suppress cell motility. Additionally, p27Kip1 interacts with the transcription factor c-Jun in the nucleus, repressing AP-1 activity and thereby modulating related to proliferation and differentiation.

Functional Networks and Pathways

The inhibitor p27Kip1, encoded by CDKN1B, integrates into several key signaling networks that regulate progression, growth arrest, and stress responses. In the PI3K/AKT pathway, stimulation activates PI3K, leading to AKT-mediated of p27Kip1 at 157 (T157) and 198 (T198), which promotes its cytoplasmic sequestration and reduces its nuclear inhibitory activity on cyclin E-CDK2 complexes, thereby facilitating G1/S transition and . This mechanism links mitogenic signals to entry, with dysregulation often observed in oncogenic contexts where hyperactive AKT impairs p27Kip1's tumor-suppressive role. In the TGF-β signaling pathway, TGF-β ligands induce receptor activation, recruiting Smad2/3 proteins that form a complex with Smad4 to translocate to the nucleus and upregulate CDKN1B transcription, thereby elevating p27Kip1 levels and enforcing G1 arrest by inhibiting CDK2 activity. Additionally, TGF-β stabilizes p27Kip1 protein through Smad-dependent inhibition of proteasomal degradation, enhancing its association with cyclin-CDK complexes to mediate cytostatic responses in epithelial and mesenchymal cells. This network underscores p27Kip1's role in TGF-β-induced growth suppression. The DNA damage response pathway positions p27Kip1 downstream of the axis, where DNA lesions activate /ATR kinases that stabilize , indirectly promoting p27Kip1 accumulation to reinforce G1 checkpoint arrest after initial p21-mediated inhibition. directly phosphorylates p27Kip1 at serine 140, enhancing its stability and CDK-inhibitory function, which is essential for sustained blockade in p53-proficient cells and prevents progression of damaged genomes. Recent investigations (2023–2025) have revealed p27Kip1's integration into networks controlling in drug-tolerant persister cells, where AKT1-mediated at serine 10 stabilizes p27Kip1, restricting endomitosis and limiting ploidy to ≤4N following mitotic inhibitors like , thereby enabling reversible in circulating tumor cells. In the context of type 4 (MEN4), germline CDKN1B mutations disrupt p27Kip1's function within endocrine signaling networks, impairing its inhibition of cyclin-CDK complexes in pituitary and parathyroid cells and leading to through dysregulated G1/S progression linked to menin-dependent transcriptional control.

References

  1. https://www.ncbi.nlm.nih.gov/gene/1027
  2. https://www.ncbi.nlm.nih.gov/omim/600778
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC8465030/
  4. https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000111276
  5. https://gtexportal.org/home/gene/CDKN1B
  6. https://pmc.ncbi.nlm.nih.gov/articles/PMC5995243/
  7. https://pmc.ncbi.nlm.nih.gov/articles/PMC6442415/
  8. https://www.nature.com/articles/382325a0
  9. https://pmc.ncbi.nlm.nih.gov/articles/PMC2643810/
  10. https://www.embopress.org/doi/10.1093/emboj/18.6.1571
  11. https://www.nature.com/articles/nsmb746
  12. https://www.jbc.org/article/S0021-9258(18)60187-5/fulltext
  13. https://www.science.org/doi/10.1126/science.aaw2106
  14. https://www.researchgate.net/publication/5459982_c-Myc_represses_FOXO3a-mediated_transcription_of_the_gene_encoding_the_p27Kip1_cyclin_dependent_kinase_inhibitor
  15. https://pmc.ncbi.nlm.nih.gov/articles/PMC6470592/
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC12568926/
  17. https://pubmed.ncbi.nlm.nih.gov/16369045/
  18. https://www.sciencedirect.com/science/article/pii/S0304419X16300294
  19. https://pmc.ncbi.nlm.nih.gov/articles/PMC1850003/
  20. https://www.molbiolcell.org/doi/10.1091/mbc.e02-06-0319
  21. https://pubmed.ncbi.nlm.nih.gov/10375532/
  22. https://www.sciencedirect.com/science/article/pii/S0960982299802905
  23. https://pubmed.ncbi.nlm.nih.gov/21423214/
  24. https://pubmed.ncbi.nlm.nih.gov/12042314/
  25. https://www.oncotarget.com/article/25447/text/
  26. https://pmc.ncbi.nlm.nih.gov/articles/PMC5943672/
  27. https://pubmed.ncbi.nlm.nih.gov/26450989/
  28. https://academic.oup.com/jnci/article/102/10/706/2516066
  29. https://erc.bioscientifica.com/view/journals/erc/14/3/0140791.xml
  30. https://pmc.ncbi.nlm.nih.gov/articles/PMC5414927/
  31. https://pubmed.ncbi.nlm.nih.gov/19153141/
  32. https://pmc.ncbi.nlm.nih.gov/articles/PMC6511791/
  33. https://www.sciencedirect.com/science/article/pii/S0021925820449993
  34. https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-018-0902-1
  35. https://www.tandfonline.com/doi/full/10.1080/21655979.2021.1982310
  36. https://www.sciencedirect.com/science/article/pii/S0092867400812374
  37. https://www.cell.com/cell/pdf/S0092-8674%2800%2981237-4.pdf
  38. https://pmc.ncbi.nlm.nih.gov/articles/PMC1852956/
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC86983/
  40. https://www.spandidos-publications.com/10.3892/br.2023.1670
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC10335976/
  42. https://genesdev.cshlp.org/content/18/8/862.long
  43. https://pmc.ncbi.nlm.nih.gov/articles/PMC5965279/
  44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685623/
  45. https://aacrjournals.org/clincancerres/article/10/5/1743/184291/Prognostic-Significance-of-p27kip-1-Expression-in
  46. https://www.pnas.org/doi/10.1073/pnas.2507203122
  47. https://pubmed.ncbi.nlm.nih.gov/15627896/
  48. https://pubmed.ncbi.nlm.nih.gov/39936980/
  49. https://pmc.ncbi.nlm.nih.gov/articles/PMC11543279/
  50. https://pmc.ncbi.nlm.nih.gov/articles/PMC2711846/
  51. https://www.sciencedirect.com/science/article/abs/pii/S1078143909000957
  52. https://academic.oup.com/jnci/article/97/2/103/2544058
  53. https://academic.oup.com/jcem/article/105/6/1983/5813889
  54. https://www.mdpi.com/2073-4409/14/3/188
  55. https://pmc.ncbi.nlm.nih.gov/articles/PMC2727647/
  56. https://pubmed.ncbi.nlm.nih.gov/9637141/
  57. https://pmc.ncbi.nlm.nih.gov/articles/PMC10817603/
  58. https://www.ncbi.nlm.nih.gov/books/NBK594826/
  59. https://pmc.ncbi.nlm.nih.gov/articles/PMC6951437/
  60. https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-022-00941-0
  61. https://pmc.ncbi.nlm.nih.gov/articles/PMC10113621/
  62. https://www.mdpi.com/2072-6694/12/5/1249
  63. https://academic.oup.com/jnci/article/90/23/1836/2521058
  64. https://www.oncotarget.com/article/28039/text/
  65. https://pmc.ncbi.nlm.nih.gov/articles/PMC3673714/
  66. https://www.nature.com/articles/s41586-025-09433-w
  67. https://clinicaltrials.gov/ct2/show/NCT06577987
  68. https://pmc.ncbi.nlm.nih.gov/articles/PMC6762752/
  69. https://onlinelibrary.wiley.com/doi/10.1155/2019/5743109
  70. https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2013.00139/full
  71. https://pmc.ncbi.nlm.nih.gov/articles/PMC5451560/
  72. https://elifesciences.org/articles/100904
  73. https://pmc.ncbi.nlm.nih.gov/articles/PMC3048746/
  74. https://journals.physiology.org/doi/full/10.1152/physrev.00021.2014
  75. https://pubmed.ncbi.nlm.nih.gov/15472992/
  76. https://www.researchgate.net/publication/8242785_Number_of_oligodendrocyte_progenitors_recruited_to_the_lesioned_spinal_cord_is_modulated_by_the_levels_of_the_cell_cycle_regulatory_protein_p27Kip-1
  77. https://pmc.ncbi.nlm.nih.gov/articles/PMC6093087/
  78. https://www.mdpi.com/2073-4409/10/6/1430
  79. https://www.jneurosci.org/content/34/47/15751
  80. https://doi.org/10.1038/382325a0
  81. https://pubmed.ncbi.nlm.nih.gov/8033212/
  82. https://doi.org/10.3390/cells10092254
  83. https://doi.org/10.1038/12013
  84. https://doi.org/10.1038/ncb1194
  85. https://pubmed.ncbi.nlm.nih.gov/10559916/
  86. https://doi.org/10.1038/nm761
  87. https://pubmed.ncbi.nlm.nih.gov/12244301/
  88. https://doi.org/10.4161/cc.6.5.3899
  89. https://pubmed.ncbi.nlm.nih.gov/15652749/
  90. https://pubmed.ncbi.nlm.nih.gov/12244303/
  91. https://pmc.ncbi.nlm.nih.gov/articles/PMC1602368/
  92. https://pubmed.ncbi.nlm.nih.gov/19221482/
  93. https://pmc.ncbi.nlm.nih.gov/articles/PMC3594702/
  94. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162806
  95. https://pmc.ncbi.nlm.nih.gov/articles/PMC12280942/
  96. https://pmc.ncbi.nlm.nih.gov/articles/PMC5623937/
Add your contribution
Related Hubs
User Avatar
No comments yet.