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]

Contents

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

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

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

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

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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Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

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DNA methylation in cancer plays a variety of roles, helping to change the healthy cells by regulation of gene expression to a cancer cells or a diseased cells disease pattern. One of the most widely studied DNA methylation dysregulation is the promoter hypermethylation where the CPGs islands in the promoter regions are methylated contributing or causing genes to be silenced.

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Epigenetics of autoimmune disorders is the role that epigenetics play in autoimmune diseases. Autoimmune disorders are a diverse class of diseases that share a common origin. These diseases originate when the immune system becomes dysregulated and mistakenly attacks healthy tissue rather than foreign invaders. These diseases are classified as either local or systemic based upon whether they affect a single body system or if they cause systemic damage.

Epigenetics of chronic pain is the study of how epigenetic modifications of genes affect the development and maintenance of chronic pain. Chromatin modifications have been found to affect neural function, such as synaptic plasticity and memory formation, which are important mechanisms of chronic pain. In 2019, 20% of adults dealt with chronic pain. Epigenetics can provide a new perspective on the biological mechanisms and potential treatments of chronic pain.

References

  1. ↑ Atkinson, Taylor J; Halfon, Marc S (2014-01-01). "Regulation of Gene Expression in the Genomic Context". Computational and Structural Biotechnology Journal. 9 (13): e201401001. doi: 10.5936/csbj.201401001 . ISSN   2001-0370. PMC   3962188 . PMID   24688749.
  2. ↑ Krupp, M; Lane, MD (25 February 1981). "On the mechanism of ligand-induced down-regulation of insulin receptor level in the liver cell". The Journal of Biological Chemistry. 256 (4): 1689–94. doi: 10.1016/S0021-9258(19)69862-5 . PMID   7007369.
  3. ↑ Zaliauskiene, Lolita; Kang, Sunghyun; Brouillette, Christie G.; Lebowitz, Jacob; Arani, Ramin B.; Collawn, James F. (2016). "Down-Regulation of Cell Surface Receptors Is Modulated by Polar Residues within the Transmembrane Domain". Molecular Biology of the Cell. 11 (8): 2643–2655. doi:10.1091/mbc.11.8.2643. ISSN   1059-1524. PMC   14946 . PMID   10930460.
  4. ↑ Carpentier, J.-L. (1994). "Insulin receptor internalization: molecular mechanisms and physiopathological implications". Diabetologia. 37 (2): S117–S124. doi: 10.1007/BF00400835 . ISSN   0012-186X. PMID   7821727.
  5. 1 2 Sherwood, Lauralee; Klandorf, Hillar; Yancey, Paul (2012-01-01). Animal Physiology: From Genes to Organisms. Cengage Learning. ISBN   978-1133709510.
  6. ↑ Fröjdö, Sara; Vidal, Hubert; Pirola, Luciano (2009-02-01). "Alterations of insulin signaling in type 2 diabetes: A review of the current evidence from humans". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1792 (2): 83–92. doi: 10.1016/j.bbadis.2008.10.019 . PMID   19041393.
  7. ↑ Wilcox, Gisela (2016-11-20). "Insulin and Insulin Resistance". Clinical Biochemist Reviews. 26 (2): 19–39. ISSN   0159-8090. PMC   1204764 . PMID   16278749.
  8. ↑ Franz, Marion J. (2000). "Protein Controversies in Diabetes". Diabetes Spectrum. 13 (3). Archived from the original on 2016-03-05. Retrieved 2016-11-20.
  9. ↑ Walker, Deena M.; Nestler, Eric J. (2018). "Neuroepigenetics and addiction". Handbook of Clinical Neurology. Vol. 148. pp. 747–765. doi:10.1016/B978-0-444-64076-5.00048-X. ISBN   9780444640765. PMC   5868351 . PMID   29478612.
  10. 1 2 Nestler, Eric J. (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 Pt B: 259–68. doi:10.1016/j.neuropharm.2013.04.004. PMC   3766384 . PMID   23643695.
  11. ↑ Bernstein, C; Prasad, AR; Nfonsam, V; Bernstein, H. (2013). "Chapter 16: DNA Damage, DNA Repair and Cancer". In Chen, Clark (ed.). New Research Directions in DNA Repair. BoD – Books on Demand. p. 413. ISBN   978-953-51-1114-6.
  12. 1 2 O'Hagan, Heather M.; Mohammad, Helai P.; Baylin, Stephen B. (15 August 2008). "Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island". PLOS Genetics. 4 (8): e1000155. doi: 10.1371/journal.pgen.1000155 . PMC   2491723 . PMID   18704159. Taken together, our data suggest that normal repair of a DNA break can occasionally cause heritable silencing of a CpG island–containing promoter by recruitment of proteins involved in silencing...This finding suggests that DNA damage may directly contribute to the large number of epigenetically silenced genes in tumors.
  13. 1 2 Cuozzo, Concetta; Porcellini, Antonio; Angrisano, Tiziana; Morano, Annalisa; Lee, Bongyong; Pardo, Alba Di; Messina, Samantha; Iuliano, Rodolfo; Fusco, Alfredo; Santillo, Maria R; Muller, Mark T; Chiariotti, Lorenzo; Gottesman, Max E; Avvedimento, Enrico V (6 July 2007). "DNA Damage, Homology-Directed Repair, and DNA Methylation". PLOS Genetics. 3 (7): e110. doi: 10.1371/journal.pgen.0030110 . PMC   1913100 . PMID   17616978. ...data support a mechanistic link between HR and DNA methylation and suggest that DNA methylation in eukaryotes marks homologous recombined segments.
  14. ↑ Baxter, Eva; Windloch, Karolina; Gannon, Frank; Lee, Jason S (December 2014). "Epigenetic regulation in cancer progression". Cell & Bioscience. 4 (1): 45. doi: 10.1186/2045-3701-4-45 . PMC   4422217 . PMID   25949794.
  15. ↑ Bilgrami, Shumaila M; Qureshi, Sohail A; Pervez, Shahid; Abbas, Farhat (December 2014). "Promoter hypermethylation of tumor suppressor genes correlates with tumor grade and invasiveness in patients with urothelial bladder cancer". SpringerPlus. 3 (1): 178. doi: 10.1186/2193-1801-3-178 . PMC   4000596 . PMID   24790823.
  16. ↑ Muvarak, Nidal; Kelley, Shannon; Robert, Carine; Baer, Maria R.; Perrotti, Danilo; Gambacorti-Passerini, Carlo; Civin, Curt; Scheibner, Kara; Rassool, Feyruz V. (1 April 2015). "c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase–Activated Leukemias". Molecular Cancer Research. 13 (4): 699–712. doi:10.1158/1541-7786.MCR-14-0422. PMC   4398615 . PMID   25828893.
  17. ↑ Newman, Erika A.; Lu, Fujia; Bashllari, Daniela; Wang, Li; Opipari, Anthony W.; Castle, Valerie P. (1 March 2015). "Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma". Molecular Cancer Research. 13 (3): 470–482. doi:10.1158/1541-7786.MCR-14-0337. PMID   25563294. S2CID   1830505.
  18. ↑ Mego, Michal; Cierna, Zuzana; Svetlovska, Daniela; Macak, Dusan; Machalekova, Katarina; Miskovska, Viera; Chovanec, Michal; Usakova, Vanda; Obertova, Jana; Babal, Pavel; Mardiak, Jozef (July 2013). "PARP expression in germ cell tumours". Journal of Clinical Pathology. 66 (7): 607–612. doi:10.1136/jclinpath-2012-201088. PMID   23486608. S2CID   535704.
  19. ↑ Newman, Robert; Soldatenkov, Viatcheslav; Dritschilo, Anatoly; Notario, Vicente (1 May 2002). "Poly(ADP-ribose) polymerase turnover alterations do not contribute to PARP overexpression in Ewing's sarcoma cells". Oncology Reports. 9 (3): 529–532. doi:10.3892/or.9.3.529. PMID   11956622.
  20. ↑ Xu, H; Zheng, L; Dai, H; Zhou, M; Hua, Y; Shen, B (2011). "Chemical-induced cancer incidence and underlying mechanisms in Fen1 mutant mice". Oncogene. 30 (9): 1072–1081. doi:10.1038/onc.2010.482. PMC   3832200 . PMID   20972458.
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