Editing Downregulation and upregulation

{{Short description|Biological processes}}

In [[biochemistry]], in the [[biology|biological]] context of [[organism]]s' [[regulation of gene expression]] and production of [[gene products]], '''downregulation''' is the process by which a [[cell (biology)|cell]] decreases the production and quantities of its [[cellular component]]s, such as [[RNA]] and [[protein]]s, in response to an external stimulus. The complementary process that involves increase in quantities of cellular components is called '''upregulation.'''<ref>{{Cite journal |last1=Atkinson |first1=Taylor J |last2=Halfon |first2=Marc S |title=Regulation of Gene Expression in the Genomic Context |date=2014-01-01 |journal=Computational and Structural Biotechnology Journal |language=en |volume=9 |issue=13 |pages=e201401001 |doi=10.5936/csbj.201401001 |pmid=24688749 |pmc=3962188 |issn=2001-0370 |doi-access=free}}</ref>

An example of downregulation is the cellular decrease in the expression of a specific [[Receptor (biochemistry)|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 [[Polychlorinated dibenzodioxins|dioxin]]. In this situation, the cells increase their production of [[cytochrome P450|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 [[epigenetics|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 [[Behavioral epigenetics#Drug addiction|drug addiction]] or [[Cancer epigenetics|progression to cancer]].

==Downregulation and upregulation of receptors==
{{More citations needed section | date = February 2020}}
All living cells have the ability to receive and process signals that originate outside their membranes, which they do by means of proteins called [[receptor (biology)|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|date=July 2024|reason=removed dead link to unreliable source}} 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 [[Endogeny (biology)|endogenous]] mediators or from [[exogeny|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 agonist]]s may cause downregulation of their respective receptors, while most [[receptor antagonist]]s temporarily upregulate their respective receptors. The disequilibrium caused by these changes often causes [[Drug withdrawal|withdrawal]] when the long-term use of a [[drug]] is discontinued.

Upregulation and downregulation can also happen as a response to [[toxin]]s or [[hormone]]s. 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.<ref>{{Cite journal |last1=Krupp |first1=M |last2=Lane |first2=MD |date=25 February 1981 |title=On the mechanism of ligand-induced down-regulation of insulin receptor level in the liver cell. |journal=The Journal of Biological Chemistry |volume=256 |issue=4 |pages=1689–94 |doi=10.1016/S0021-9258(19)69862-5 |doi-access=free |pmid=7007369}}</ref> 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]].<ref>{{Cite journal |last1=Zaliauskiene |first1=Lolita |last2=Kang |first2=Sunghyun |last3=Brouillette |first3=Christie G. |last4=Lebowitz |first4=Jacob |last5=Arani |first5=Ramin B. |last6=Collawn |first6=James F. |date=2016 |title=Down-Regulation of Cell Surface Receptors Is Modulated by Polar Residues within the Transmembrane Domain |journal=Molecular Biology of the Cell |volume=11 |issue=8 |pages=2643–2655 |doi=10.1091/mbc.11.8.2643 |issn=1059-1524 |pmc=14946 |pmid=10930460}}</ref> 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.<ref>{{Cite journal |last=Carpentier |first=J.-L. |year=1994 |title=Insulin receptor internalization: molecular mechanisms and physiopathological implications |journal=Diabetologia |language=en |volume=37 |issue=2 |pages=S117–S124 |doi=10.1007/BF00400835 |issn=0012-186X |pmid=7821727 |doi-access=free}}</ref> 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.<ref name=":0">{{Cite book |last1=Sherwood |first1=Lauralee |url=https://books.google.com/books?id=BR8KAAAAQBAJ&q=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&pg=PA278 |title=Animal Physiology: From Genes to Organisms |last2=Klandorf |first2=Hillar |last3=Yancey |first3=Paul |date=2012-01-01 |publisher=Cengage Learning |isbn=978-1133709510 |language=en}}</ref>{{Page needed|date=July 2024}} The rate of [[Biosynthesis|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.<ref name=":0" />

This process is illustrated by the [[insulin]] receptor sites on target cells, e.g. liver cells, in a person with type 2 [[diabetes]].<ref>{{Cite journal |last1=Fröjdö |first1=Sara |last2=Vidal |first2=Hubert |last3=Pirola |first3=Luciano |date=2009-02-01 |title=Alterations of insulin signaling in type 2 diabetes: A review of the current evidence from humans |journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease |volume=1792 |issue=2 |pages=83–92 |doi=10.1016/j.bbadis.2008.10.019 |pmid=19041393 |doi-access=free}}</ref> Due to the elevated levels of blood [[glucose]] in an individual, the [[beta cell|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.<ref>{{Cite journal |last=Wilcox |first=Gisela |date=2016-11-20 |title=Insulin and Insulin Resistance |journal=Clinical Biochemist Reviews |volume=26 |issue=2 |pages=19–39 |issn=0159-8090 |pmc=1204764 |pmid=16278749}}</ref> 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|date=December 2016}} 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.<ref>{{Cite journal |last=Franz |first=Marion J. |year=2000 |title=Protein Controversies in Diabetes |url=http://journal.diabetes.org/diabetesspectrum/00v13n3/pg132.htm |journal=Diabetes Spectrum |volume=13 |issue=3 |archive-url=https://web.archive.org/web/20160305170740/http://journal.diabetes.org/diabetesspectrum/00v13n3/pg132.htm |archive-date=2016-03-05 |access-date=2016-11-20}}</ref>

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.<ref name="Walker2018">{{cite book |last1=Walker |first1=Deena M. |last2=Nestler |first2=Eric J. |chapter=Neuroepigenetics and addiction |title=Handbook of Clinical Neurology |date=2018 |volume=148 |pages=747–765 |doi=10.1016/B978-0-444-64076-5.00048-X |pmid=29478612 |pmc=5868351 |isbn=9780444640765 }}</ref>

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 [[microRNA]]s through [[epigenetics|epigenetic alterations]].<ref name=Nestler2014>{{cite journal |last1=Nestler |first1=Eric J. |title=Epigenetic mechanisms of drug addiction |journal=Neuropharmacology |volume=76 Pt B |pages=259–68 |date=January 2014 |pmid=23643695 |pmc=3766384 |doi=10.1016/j.neuropharm.2013.04.004 }}</ref> Such downregulation or upregulation has been shown to occur in the brain's reward regions, such as the [[nucleus accumbens]].<ref name=Nestler2014 />

==Cancer==
{{See also|Regulation of transcription in cancer}}
DNA damage appears to be the primary underlying cause of cancer.<ref name=BernsteinPrasad>{{cite book |last1= Bernstein |first1=C |last2=Prasad |first2=AR |last3=Nfonsam |first3=V |last4=Bernstein |first4=H. |year=2013 |chapter= Chapter 16: DNA Damage, DNA Repair and Cancer |title= New Research Directions in DNA Repair |editor-first=Clark |editor-last=Chen |isbn=978-953-51-1114-6|page=413|publisher=BoD – Books on Demand }}</ref> DNA damage can also increase [[epigenetic]] alterations due to errors during DNA repair.<ref name="O'Hagan2008">{{cite journal |last1=O'Hagan |first1=Heather M. |last2=Mohammad |first2=Helai P. |last3=Baylin |first3=Stephen B. |title=Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island |journal=PLOS Genetics |date=15 August 2008 |volume=4 |issue=8 |pages=e1000155 |doi=10.1371/journal.pgen.1000155 |pmid=18704159 |pmc=2491723 |doi-access=free |quote=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. }}</ref><ref name="Cuozzo2007">{{cite journal |last1=Cuozzo |first1=Concetta |last2=Porcellini |first2=Antonio |last3=Angrisano |first3=Tiziana |last4=Morano |first4=Annalisa |last5=Lee |first5=Bongyong |last6=Pardo |first6=Alba Di |last7=Messina |first7=Samantha |last8=Iuliano |first8=Rodolfo |last9=Fusco |first9=Alfredo |last10=Santillo |first10=Maria R |last11=Muller |first11=Mark T |last12=Chiariotti |first12=Lorenzo |last13=Gottesman |first13=Max E |last14=Avvedimento |first14=Enrico V |title=DNA Damage, Homology-Directed Repair, and DNA Methylation |journal=PLOS Genetics |date=6 July 2007 |volume=3 |issue=7 |pages=e110 |doi=10.1371/journal.pgen.0030110 |pmid=17616978 |pmc=1913100 |doi-access=free |quote=...data support a mechanistic link between HR and DNA methylation and suggest that DNA methylation in eukaryotes marks homologous recombined segments.}}</ref> Such mutations and epigenetic alterations can give rise to [[cancer]] (see [[Neoplasm#Malignant neoplasms|malignant neoplasms]]).<ref name="O'Hagan2008" /><ref name="Cuozzo2007" />{{Verify source<!-- Both references supplied talked about the silencing of the genes that were repaired, but the references seem highly technical, someone please check. Clarification also would be appreciated. [Note from 2nd editor in July 2022: added quotes to cites, but changed statement from "is likely central to progression to cancer" as that is too strong going by sources used.]-->| date = June 2020 }} Investigation of epigenetic down- or upregulation of repaired DNA genes as possibly central to progression of cancer has been regularly undertaken since 2000.<ref>{{cite journal |last1=Baxter |first1=Eva |last2=Windloch |first2=Karolina |last3=Gannon |first3=Frank |last4=Lee |first4=Jason S |title=Epigenetic regulation in cancer progression |journal=Cell & Bioscience |date=December 2014 |volume=4 |issue=1 |pages=45 |doi=10.1186/2045-3701-4-45|pmid=25949794 |pmc=4422217 |doi-access=free }}</ref>

Epigenetic downregulation of the DNA repair gene ''[[O-6-methylguanine-DNA methyltransferase|MGMT]]'' occurs in 93% of bladder cancers,<ref>{{cite journal |last1=Bilgrami |first1=Shumaila M |last2=Qureshi |first2=Sohail A |last3=Pervez |first3=Shahid |last4=Abbas |first4=Farhat |title=Promoter hypermethylation of tumor suppressor genes correlates with tumor grade and invasiveness in patients with urothelial bladder cancer |journal=SpringerPlus |date=December 2014 |volume=3 |issue=1 |pages=178 |doi=10.1186/2193-1801-3-178|pmid=24790823 |pmc=4000596 |doi-access=free }}</ref> 88% of stomach cancers, 74% of thyroid cancers, 40&ndash;90% of colorectal cancers, and 50% of brain cancers.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} Similarly, epigenetic downregulation of ''[[LIG4]]'' occurs in 82% of colorectal cancers and epigenetic downregulation of ''[[NEIL1]]'' occurs in 62% of [[head and neck cancer]]s and in 42% of [[non-small-cell lung carcinoma|non-small-cell lung cancer]]s.

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,<ref>{{cite journal |last1=Muvarak |first1=Nidal |last2=Kelley |first2=Shannon |last3=Robert |first3=Carine |last4=Baer |first4=Maria R. |last5=Perrotti |first5=Danilo |last6=Gambacorti-Passerini |first6=Carlo |last7=Civin |first7=Curt |last8=Scheibner |first8=Kara |last9=Rassool |first9=Feyruz V. |title=c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase–Activated Leukemias |journal=Molecular Cancer Research |date=1 April 2015 |volume=13 |issue=4 |pages=699–712 |doi=10.1158/1541-7786.MCR-14-0422|pmid=25828893 |pmc=4398615 }}</ref> in neuroblastoma,<ref>{{cite journal |last1=Newman |first1=Erika A. |last2=Lu |first2=Fujia |last3=Bashllari |first3=Daniela |last4=Wang |first4=Li |last5=Opipari |first5=Anthony W. |last6=Castle |first6=Valerie P. |title=Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma |journal=Molecular Cancer Research |date=1 March 2015 |volume=13 |issue=3 |pages=470–482 |doi=10.1158/1541-7786.MCR-14-0337|pmid=25563294 |s2cid=1830505 |url=https://figshare.com/articles/journal_contribution/22517004 }}</ref> in testicular and other germ cell tumors,<ref>{{cite journal |last1=Mego |first1=Michal |last2=Cierna |first2=Zuzana |last3=Svetlovska |first3=Daniela |last4=Macak |first4=Dusan |last5=Machalekova |first5=Katarina |last6=Miskovska |first6=Viera |last7=Chovanec |first7=Michal |last8=Usakova |first8=Vanda |last9=Obertova |first9=Jana |last10=Babal |first10=Pavel |last11=Mardiak |first11=Jozef |title=PARP expression in germ cell tumours |journal=Journal of Clinical Pathology |date=July 2013 |volume=66 |issue=7 |pages=607–612 |doi=10.1136/jclinpath-2012-201088|pmid=23486608 |s2cid=535704 }}</ref> and in Ewing's sarcoma.<ref>{{cite journal |last1=Newman |first1=Robert |last2=Soldatenkov |first2=Viatcheslav |last3=Dritschilo |first3=Anatoly |last4=Notario |first4=Vicente |title=Poly(ADP-ribose) polymerase turnover alterations do not contribute to PARP overexpression in Ewing's sarcoma cells |journal=Oncology Reports |date=1 May 2002 |volume=9 |issue=3 |pages=529–532 |doi=10.3892/or.9.3.529|pmid=11956622 }}</ref> [[FEN1]] is upregulated in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreas, and lung.<ref>{{cite journal |last1=Xu |first1=H |last2=Zheng |first2=L |last3=Dai |first3=H |last4=Zhou |first4=M |last5=Hua |first5=Y |last6=Shen |first6=B |title=Chemical-induced cancer incidence and underlying mechanisms in Fen1 mutant mice. |journal=Oncogene |date=2011 |volume=30 |issue=9 |pages=1072–1081|doi=10.1038/onc.2010.482 |pmid=20972458 |pmc=3832200 }}</ref> {{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}

==See also==
* [[Regulation of gene expression]]
* [[Transcriptional regulation]]
* [[Enhancer (genetics)]]


==References==
{{Reflist}}

==External links==
* {{MeshName|Down-Regulation}}

{{Molecular Biology}}

[[Category:Molecular biology]]
[[Category:Genetics]]
[[Category:Cell biology]]