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Downregulation and upregulation
Downregulation and upregulation
Downregulation and upregulation
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In biochemistry, in the biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell decreases the production and quantities of its cellular components, such as RNA and proteins, in response to an external stimulus. The complementary process that involves increase in quantities of cellular components is called upregulation.[1]

An example of downregulation is the cellular decrease in the expression of a specific receptor in response to its increased activation by a molecule, such as a hormone or neurotransmitter, which reduces the cell's sensitivity to the molecule. This is an example of a locally acting (negative feedback) mechanism.

An example of upregulation is the response of liver cells exposed to such xenobiotic molecules as dioxin. In this situation, the cells increase their production of cytochrome P450 enzymes, which in turn increases degradation of these dioxin molecules.

Downregulation or upregulation of an RNA or protein may also arise by an epigenetic alteration. Such an epigenetic alteration can cause expression of the RNA or protein to no longer respond to an external stimulus. This occurs, for instance, during drug addiction or progression to cancer.

Downregulation and upregulation of receptors

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All living cells have the ability to receive and process signals that originate outside their membranes, which they do by means of proteins called receptors, often located at the cell's surface imbedded in the plasma membrane. When such signals interact with a receptor, they effectively direct the cell to do something, such as dividing, dying, or allowing substances to be created, or to enter or exit the cell. A cell's ability to respond to a chemical message depends on the presence of receptors tuned to that message. The more receptors a cell has that are tuned to the message, the more the cell will respond to it.

Receptors are created, or expressed, from instructions in the DNA of the cell, and they can be increased, or upregulated, when the signal is weak, or decreased, or downregulated, when it is strong.[citation needed] Their level can also be up or down regulated by modulation of systems that degrade receptors when they are no longer required by the cell.

Downregulation of receptors can also occur when receptors have been chronically exposed to an excessive amount of a ligand, either from endogenous mediators or from exogenous drugs. This results in ligand-induced desensitization or internalization of that receptor. This is typically seen in animal hormone receptors. Upregulation of receptors, on the other hand, can result in super-sensitized cells, especially after repeated exposure to an antagonistic drug or prolonged absence of the ligand.

Some receptor agonists may cause downregulation of their respective receptors, while most receptor antagonists temporarily upregulate their respective receptors. The disequilibrium caused by these changes often causes withdrawal when the long-term use of a drug is discontinued.

Upregulation and downregulation can also happen as a response to toxins or hormones. An example of upregulation in pregnancy is hormones that cause cells in the uterus to become more sensitive to oxytocin.

Example: Insulin receptor downregulation

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Elevated levels of the hormone insulin in the blood trigger downregulation of the associated receptors.[2] When insulin binds to its receptors on the surface of a cell, the hormone receptor complex undergoes endocytosis and is subsequently attacked by intracellular lysosomal enzymes.[3] The internalization of the insulin molecules provides a pathway for degradation of the hormone, as well as for regulation of the number of sites that are available for binding on the cell surface.[4] At high plasma concentrations, the number of surface receptors for insulin is gradually reduced by the accelerated rate of receptor internalization and degradation brought about by increased hormonal binding.[5][page needed] The rate of synthesis of new receptors within the endoplasmic reticulum and their insertion in the plasma membrane do not keep pace with their rate of destruction. Over time, this self-induced loss of target cell receptors for insulin reduces the target cell's sensitivity to the elevated hormone concentration.[5]

This process is illustrated by the insulin receptor sites on target cells, e.g. liver cells, in a person with type 2 diabetes.[6] Due to the elevated levels of blood glucose in an individual, the β-cells (islets of Langerhans) in the pancreas must release more insulin than normal to meet the demand and return the blood to homeostatic levels.[7] The near-constant increase in blood insulin levels results from an effort to match the increase in blood glucose, which will cause receptor sites on the liver cells to downregulate and decrease the number of receptors for insulin, increasing the subject's resistance by decreasing sensitivity to this hormone.[citation needed] There is also a hepatic decrease in sensitivity to insulin. This can be seen in the continuing gluconeogenesis in the liver even when blood glucose levels are elevated. This is the more common process of insulin resistance, which leads to adult-onset diabetes.[8]

Another example can be seen in diabetes insipidus, in which the kidneys become insensitive to arginine vasopressin.

Drug addiction

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Family-based, adoption, and twin studies have indicated that there is a strong (50%) heritable component to vulnerability to substance abuse addiction.[9]

Especially among genetically vulnerable individuals, repeated exposure to a drug of abuse in adolescence or adulthood causes addiction by inducing stable downregulation or upregulation in expression of specific genes and microRNAs through epigenetic alterations.[10] Such downregulation or upregulation has been shown to occur in the brain's reward regions, such as the nucleus accumbens.[10]

Cancer

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See also: Regulation of transcription in cancer

DNA damage appears to be the primary underlying cause of cancer.[11] DNA damage can also increase epigenetic alterations due to errors during DNA repair.[12][13] Such mutations and epigenetic alterations can give rise to cancer (see malignant neoplasms).[12][13][verification needed] Investigation of epigenetic down- or upregulation of repaired DNA genes as possibly central to progression of cancer has been regularly undertaken since 2000.[14]

Epigenetic downregulation of the DNA repair gene MGMT occurs in 93% of bladder cancers,[15] 88% of stomach cancers, 74% of thyroid cancers, 40–90% of colorectal cancers, and 50% of brain cancers.[citation needed] Similarly, epigenetic downregulation of LIG4 occurs in 82% of colorectal cancers and epigenetic downregulation of NEIL1 occurs in 62% of head and neck cancers and in 42% of non-small-cell lung cancers.

Epigenetic upregulation of the DNA repair genes PARP1 and FEN1 occurs in numerous cancers (see Regulation of transcription in cancer). PARP1 and FEN1 are essential genes in the error-prone and mutagenic DNA repair pathway microhomology-mediated end joining. If this pathway is upregulated, the excess mutations it causes can lead to cancer. PARP1 is over-expressed in tyrosine kinase-activated leukemias,[16] in neuroblastoma,[17] in testicular and other germ cell tumors,[18] and in Ewing's sarcoma.[19] FEN1 is upregulated in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreas, and lung.[20] [citation needed]

See also

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References

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Downregulation and upregulation

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from Grokipedia
In , downregulation refers to the decrease in the number of receptors on a cell surface or the reduction in the level of , while upregulation denotes the opposite process of increasing receptor density or enhancing in response to specific stimuli. These regulatory mechanisms allow cells to adjust their sensitivity to signaling molecules, such as hormones or neurotransmitters, and to fine-tune protein production based on environmental or internal cues. Downregulation often occurs through processes like receptor internalization and degradation via , particularly for G-protein-coupled receptors (GPCRs), leading to diminished cellular responsiveness over hours or days; recovery typically requires new receptor synthesis. In contrast, upregulation can involve transcriptional , where transcription factors bind to promoter regions to boost mRNA synthesis and subsequent protein levels. For , these processes are mediated by factors such as microRNAs, which can either repress (downregulate) or, in some cases, enhance (upregulate) target gene activity by influencing mRNA stability or translation. These mechanisms are crucial for maintaining , responding to physiological demands, and preventing overstimulation; dysregulation of upregulation or downregulation is implicated in diseases like cancer, where genes controlling may be aberrantly upregulated, or in cardiovascular conditions involving altered endothelial nitric oxide synthase (eNOS) expression. Examples include the downregulation of aquaporin-4 (AQP4) channels in to reduce water influx, or the upregulation of eNOS by statins to improve vascular function. Overall, downregulation and upregulation enable dynamic control over cellular functions, ensuring adaptability in multicellular organisms.

Fundamental Concepts

Definition of Downregulation

Downregulation is a biological process characterized by a decrease in the number, sensitivity, or activity of cellular components, such as receptors, enzymes, or genes, in response to prolonged or excessive stimulation by a ligand or other signal. This reduction serves as a negative regulatory mechanism at the molecular, cellular, or systemic level, modulating physiological responses to prevent cellular overload. In receptor biology, downregulation typically manifests as a diminished density of receptors on the cell surface through mechanisms like internalization, thereby lowering the cell's responsiveness to the stimulating agent. The process applies across various contexts, including alterations in protein levels—such as receptor on the plasma membrane—and reductions in signaling pathway activity following sustained exposure. It can also influence mRNA transcription and protein synthesis rates, thereby adjusting overall to maintain . For instance, in systems, downregulation modulates the quantity of receptors available in neural circuits, fine-tuning synaptic transmission. These adaptations are often reversible upon removal of the stimulus but may lead to persistent changes under chronic conditions. The term "downregulation" was coined in the 1970s within the fields of and to describe these adaptive responses in signaling pathways, with early descriptions emerging from studies on receptors and their by ligands. Seminal work by et al. in 1972 demonstrated insulin-induced decreases in number on cell surfaces, establishing downregulation as a key homeostatic process in receptor biology. Subsequent studies by , , and Lefkowitz in the mid-1970s extended this to beta-adrenergic receptors and their by catecholamines. This concept contrasts with upregulation, which involves an increase in cellular responsiveness.

Definition of Upregulation

Upregulation is a fundamental in which cells increase the number, sensitivity, or activity of specific cellular components, such as receptors, ion transporters, or enzymes, to enhance responsiveness to external signals or internal needs. This adaptation typically arises in response to insufficient by ligands, chronic low-level exposure to agonists, or compensatory demands during physiological stress, thereby amplifying downstream signaling pathways to maintain . The process manifests in various contexts, including elevated protein synthesis through transcriptional activation of genes, enhanced receptor trafficking from intracellular stores to the plasma membrane, and post-translational modifications that boost component efficacy. For instance, in receptor systems, upregulation can heighten by increasing available binding sites for ligands. Upregulation serves as the counterpart to downregulation, which reduces cellular responsiveness through component loss or inactivation. The concept of upregulation emerged alongside downregulation in the , stemming from pioneering studies on receptor dynamics, particularly beta-adrenergic receptors, where reduced exposure led to compensatory increases in receptor density. Key characteristics include its role in promoting heightened cellular signaling, with short-term effects often mediated by rapid changes such as increased receptor trafficking to the cell surface or to enhance sensitivity, and long-term effects involving of proteins. This regulation is crucial in contexts such as embryonic development, tissue repair, and environmental adaptation, allowing cells to fine-tune responses to fluctuating stimuli.

Mechanisms of Regulation

Receptor-Level Mechanisms

Receptor downregulation at the protein level occurs through post-translational modifications and trafficking events that reduce surface expression and signaling capacity, particularly in G protein-coupled receptors (GPCRs). activation triggers of the receptor's intracellular domains by GPCR kinases (GRKs), such as GRK2 and GRK3, which preferentially target and residues. This serves as a signal for the recruitment of β-arrestins, multifunctional adaptor proteins that bind to the phosphorylated receptor, uncoupling it from heterotrimeric G proteins and thereby terminating G protein-mediated signaling—a process known as desensitization. Following β-arrestin binding, the receptor-β-arrestin complex interacts with and the AP-2, facilitating rapid through clathrin-coated pits at the plasma membrane. Internalized receptors traffic to early endosomes, where they face a sorting decision: some are directed to late endosomes and lysosomes for proteolytic degradation by enzymes like cathepsins, leading to a net loss of total receptor protein, while others may be targeted for . In scenarios of sustained exposure, lysosomal degradation is favored, and mechanisms such as ubiquitination of the receptor or β-arrestin promote sorting away from pathways, inhibiting return to the cell surface. These processes contribute to loops that prevent excessive signaling and maintain in GPCR pathways. Receptor can be dramatically shortened post-stimulation, dropping from several hours in the basal state to as little as minutes upon challenge, as seen in certain adenosine receptors. Chronic exposure often results in substantial reductions in receptor , with losses ranging from 50% to over 90% depending on the receptor subtype and duration of stimulation, such as in H2 receptors where approximately 50% density reduction occurs after prolonged treatment. Upregulation at the receptor level reverses these processes through and trafficking restoration. In endosomal compartments, protein phosphatases like protein phosphatase 2A (PP2A) remove the GRK-mediated phosphates from internalized receptors, enabling dissociation of β-arrestin and resensitization for renewed coupling. Dephosphorylated receptors are then sorted into recycling endosomes, often via Rab GTPases such as Rab4 and Rab11, and trafficked back to the plasma , thereby increasing surface receptor density. Under low conditions, enhanced trafficking of existing receptors to the , coupled with reduced and degradation rates, further promotes upregulation to restore signaling sensitivity. These dynamics ensure adaptive regulation without relying on new protein synthesis.

Gene Expression-Level Mechanisms

Gene expression-level mechanisms of downregulation and upregulation primarily involve alterations in transcription, translation, and mRNA stability, leading to changes in levels. These processes occur at the genomic and post-transcriptional levels, contrasting with faster post-translational modifications at the receptor level, such as , which provide immediate responses. In eukaryotes, transcriptional control is mediated by transcription factors binding to promoter regions, influencing the recruitment of and the environment around genes. Downregulation at the gene expression level can occur through several mechanisms that reduce mRNA production or stability. Repressor proteins bind to specific DNA sequences in promoter regions, blocking the access of activator proteins or , thereby inhibiting transcription initiation. For instance, in eukaryotic systems, repressors like those in the Polycomb group recruit chromatin-modifying complexes to silence genes. deacetylation, catalyzed by histone deacetylases (HDACs), removes acetyl groups from residues on histone tails, promoting compaction and transcriptional repression; this mechanism is prevalent in during development and is dysregulated in diseases like cancer. MicroRNAs (miRNAs) contribute to downregulation post-transcriptionally by binding to target mRNAs, recruiting the (RISC) to induce mRNA degradation or translational repression; miRNAs can suppress hundreds of targets, fine-tuning expression levels across cellular states. Additionally, ubiquitination targets transcription factors for proteasomal degradation; for example, E3 ligases like ubiquitinate , reducing its levels and thereby downregulating p53-dependent genes involved in arrest. These mechanisms often result in reductions in , as observed in promoter variant studies. Upregulation mechanisms enhance transcription or mRNA longevity to increase protein output. Activator proteins, such as , bind to enhancer or promoter elements, recruiting co-activators and to stimulate transcription; activation, for example, drives inflammatory by decompacting . Chromatin remodeling through histone acetylation, performed by histone acetyltransferases (HATs) like p300/CBP, neutralizes positive charges on histones, loosening structure and facilitating access to transcriptional machinery at promoters and enhancers. Enhancer activation involves distal DNA elements looping to promoters via mediator complexes, amplifying transcription of target genes in a tissue-specific manner. Post-transcriptionally, RNA-binding proteins (RBPs) stabilize mRNA by protecting it from degradation; for instance, certain RBPs bind AU-rich elements in 3' UTRs to extend mRNA , boosting expression of growth-related genes. These processes can yield fold increases in transcriptional output, depending on activator affinity and state. Gene expression-level operates on slower timescales than receptor modifications, typically spanning hours to days, allowing for sustained adaptations like differentiation or stress responses. Transcriptional changes, such as those in environmental stress responses, manifest as transient mRNA increases peaking within hours and resolving over days. Epigenetic modifications, including , provide long-term effects by adding methyl groups to CpG islands in promoters, stably repressing transcription across cell divisions via maintenance by ; this mark ensures heritable silencing, as seen in developmental inactivation. In eukaryotes, operon-like occurs through topological associations of paralogous genes via elements, enabling coordinated expression akin to bacterial operons but via looping, with observed fold changes in expression levels during stress or development.

Physiological Examples

Insulin Receptor Regulation

In insulin signaling, the (IR) undergoes downregulation during chronic , a state characterized by persistently elevated insulin levels, which promotes receptor internalization via clathrin-dependent and subsequent lysosomal degradation, thereby reducing the number of cell-surface receptors and attenuating insulin sensitivity. This process was first demonstrated in cultured human lymphocytes exposed to physiological insulin concentrations (10^{-8} M) for 5-16 hours, resulting in a significant decrease in receptor binding sites per cell, establishing a reciprocal relationship between extracellular insulin levels and receptor density. In the context of onset, —often an early compensatory response to peripheral —exacerbates the condition by inducing IR downregulation in tissues like and adipocytes, leading to impaired and contributing to . Conversely, upregulation of the IR occurs during to enhance insulin sensitivity and facilitate efficient glucose when insulin levels are low. This adaptive increase in receptor expression is mediated by the FOXO1, which, in its dephosphorylated active form during nutrient deprivation, binds to a FOXO recognition element in the IR promoter, elevating IR mRNA and protein levels in cells such as hepatocytes and myocytes. At the cellular level, these regulatory dynamics directly influence the PI3K-Akt pathway, a core mediator of insulin's metabolic effects; downregulation diminishes pathway activation, reducing translocation and synthesis via impaired Akt of glycogen synthase kinase-3, while upregulation potentiates these responses to promote anabolic processes like hepatic storage.

Adrenergic Receptor Regulation

Adrenergic receptors, a class of G protein-coupled receptors activated by catecholamines such as norepinephrine and epinephrine, undergo downregulation and upregulation to modulate responses in various physiological contexts. These regulatory processes help maintain in cardiovascular function and stress adaptation by altering receptor density, signaling efficiency, and cellular responsiveness. In conditions, beta-adrenergic receptors, particularly the β2 subtype, experience desensitization through by (PKA) and subsequent recruitment of β-arrestin, which promotes receptor and internalization. This mechanism reduces the receptors' coupling to G proteins, thereby diminishing cAMP production via and attenuating responsiveness to sustained catecholamine exposure. Such downregulation prevents excessive sympathetic activation that could lead to cardiac overload during prolonged stress. Conversely, upregulation occurs in scenarios of adrenergic , where α1-adrenergic receptor increases following sympathectomy to compensate for reduced norepinephrine levels. This adaptive rise in receptor expression enhances postsynaptic sensitivity, restoring contractile responses in tissues like the myocardium and vasculature. For instance, chemical sympathetic in models sustains elevated α1A-adrenoceptor levels, supporting compensatory signaling through proteins and pathways. Seminal studies from the 1980s, including those by Bristow et al., demonstrated significant β-adrenergic receptor loss in models, with β1 receptor density reduced by 40-60% due to chronic catecholamine stimulation, alongside uncoupling from Gs proteins and diminished cAMP signaling. These findings highlighted how downregulation contributes to blunted inotropic responses, a hallmark of failing hearts. Physiologically, these regulatory dynamics profoundly influence the , where acute upregulation sharpens sympathetic signaling for rapid cardiovascular adjustments, while chronic downregulation mitigates overstimulation. In exercise training, upregulation or enhanced β-adrenergic responsiveness facilitates recovery by improving and vascular adaptations, countering age- or disease-related desensitization.

Pathological Implications

Drug Addiction and Tolerance

In drug addiction, repeated exposure to opioids such as leads to the downregulation of mu-opioid receptors, a key neuroadaptation contributing to tolerance. This process involves receptor internalization and reduced receptor density in brain regions like the and , necessitating higher doses to achieve effects. Studies in animal models demonstrate that chronic administration induces tolerance alongside mu-opioid receptor downregulation, with no similar changes observed for delta- or kappa-opioid receptors. During withdrawal from addictive substances, compensatory mechanisms can result in dopamine supersensitivity, particularly involving D2 receptors in the , which heightens responsiveness to drug cues and drives craving. This supersensitivity emerges shortly after , enhancing behavioral responses to dopamine agonists and contributing to the motivational pull toward . In models, this adaptation reflects a hypofunctioning reward pathway, where reduced baseline dopamine signaling amplifies cue-induced craving during . Neuroplastic changes in , including those mediated by CREB (cAMP response element-binding protein) in the , underlie long-term reward pathway hypofunction. Chronic drug exposure activates CREB, promoting changes such as increased dynorphin that oppose signaling, leading to tolerance and dependence. Seminal work from the and early by Eric Nestler linked these CREB-regulated adaptations to diminished sensitivity to natural rewards and persistent motivational deficits in . These receptor dysregulations explain the escalating use seen in tolerance and play a partial role in , often via upregulated stress systems like corticotropin-releasing factor (CRF) receptors in the extended . Enhanced CRF1 receptor expression post-dependence heightens anxiety-like states and facilitates stress- or cue-induced reinstatement of drug-seeking behavior. CRF antagonists can selectively attenuate these triggers, highlighting the system's role in the negative emotional aspects of .

Cancer and Oncogenic Signaling

In cancer, dysregulation of signaling pathways through upregulation of oncogenes plays a central role in promoting tumorigenesis and tumor progression. For instance, overexpression of the (EGFR) often occurs via , leading to constitutive of downstream pathways such as the (MAPK) cascade, which drives uncontrolled and survival. This EGFR upregulation is observed in over 60% of non-small cell lung cancers (NSCLCs), contributing significantly to oncogenic signaling in these malignancies. Similarly, amplification of the human epidermal growth factor receptor 2 (HER2) gene, detected in 15-25% of cancers, enhances and through of similar tyrosine kinase-dependent pathways. Downregulation of tumor suppressor pathways further exacerbates oncogenic signaling by removing critical checkpoints on progression. A key example is the attenuation of the pathway, where upregulation of —an ubiquitin ligase—promotes the proteasomal degradation of , thereby inhibiting its transcriptional activity that normally induces arrest, , and in response to oncogenic stress. This -mediated downregulation of function allows cancer cells to evade surveillance mechanisms, facilitating unchecked proliferation and genomic instability across various tumor types. Therapeutic strategies targeting these dysregulations have revolutionized by restoring balanced signaling. Tyrosine kinase inhibitors (TKIs) like specifically block upregulated oncogenic kinases, such as BCR-ABL in chronic myeloid leukemia, thereby reversing aberrant proliferation signals and inducing remission in responsive patients. In the 2000s, discoveries regarding HER2 amplification led to the development of targeted therapies like , which binds the extracellular domain of HER2 to inhibit its signaling, improving outcomes in HER2-positive breast cancers by counteracting the proliferative effects of . Within the , upregulation of (VEGF) receptors on endothelial cells promotes pathological , enabling nutrient supply and metastatic spread. This VEGFR overexpression, driven by tumor-secreted VEGF ligands, remodels the vascular architecture to support hypoxia adaptation and immune evasion, underscoring its role as a key facilitator of oncogenic progression.

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