Editing GSK-3 (section)

==Disease relevance==

Due to its involvement in a great number of signaling pathways, GSK-3 has been associated with a host of high-profile diseases. GSK-3 inhibitors are currently being tested for therapeutic effects in [[Alzheimer's disease]], [[type 2 diabetes mellitus]] (T2DM), some forms of [[cancer]], and [[bipolar disorder]].<ref name="Saraswati_2017">{{cite journal | vauthors = Saraswati AP, Ali Hussaini SM, Krishna NH, Babu BN, Kamal A | title = Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditions | journal = European Journal of Medicinal Chemistry | volume = 144 | pages = 843–858 | date = January 2018 | pmid = 29306837 | doi = 10.1016/j.ejmech.2017.11.103 }}</ref>

There is evidence that [[Lithium (medication)|lithium]], which is used as a treatment for [[bipolar disorder]], acts as a mood stabilizer by selectively inhibiting GSK-3. The mechanism through which GSK-3 inhibition may stabilize mood is not known, though it is suspected that the inhibition of GSK-3's ability to promote inflammation contributes to the therapeutic effect.<ref name="pmid16944320"/> Inhibition of GSK-3 also destabilises Rev-ErbA alpha transcriptional repressor, which has a significant role in the circadian clock.<ref>{{cite journal | vauthors = Yin L, Wang J, Klein PS, Lazar MA | title = Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock | journal = Science | volume = 311 | issue = 5763 | pages = 1002–1005 | date = February 2006 | pmid = 16484495 | doi = 10.1126/science.1121613 | s2cid = 11240826 | bibcode = 2006Sci...311.1002Y }}</ref> Elements of the circadian clock may be connected with predisposition to bipolar mood disorder.<ref>{{cite journal | vauthors = Rybakowski JK, Dmitrzak-Weglarz M, Dembinska-Krajewska D, Hauser J, Akiskal KK, Akiskal HH | title = Polymorphism of circadian clock genes and temperamental dimensions of the TEMPS-A in bipolar disorder | journal = Journal of Affective Disorders | volume = 159 | pages = 80–84 | date = April 2014 | pmid = 24679394 | doi = 10.1016/j.jad.2014.02.024 }}</ref>

GSK-3 activity has been associated with both pathological features of Alzheimer's disease, namely the buildup of [[Beta amyloid|amyloid-β]] (Aβ) deposits and the formation of [[neurofibrillary tangle]]s. GSK-3 is thought to directly promote Aβ production and to be tied to the process of the [[hyperphosphorylation]] of [[tau protein]]s, which leads to the tangles.<ref name="pmid15102436"/><ref name="pmid16944320"/> Due to these roles of GSK-3 in promoting Alzheimer's disease, GSK-3 inhibitors may have positive therapeutic effects on Alzheimer's patients and are currently in the early stages of testing.<ref name="pmid19038340">{{cite journal | vauthors = Hu S, Begum AN, Jones MR, Oh MS, Beech WK, Beech BH, Yang F, Chen P, Ubeda OJ, Kim PC, Davies P, Ma Q, Cole GM, Frautschy SA | display-authors = 6 | title = GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals | journal = Neurobiology of Disease | volume = 33 | issue = 2 | pages = 193–206 | date = February 2009 | pmid = 19038340 | pmc = 4313761 | doi = 10.1016/j.nbd.2008.10.007 }}</ref>

In a similar fashion, targeted inhibition of GSK-3 may have therapeutic effects on certain kinds of cancer. Though GSK-3 has been shown to promote [[apoptosis]] in some cases, it has also been reported to be a key factor in [[tumorigenesis]] in some cancers.<ref name="Wang2008">{{cite journal | vauthors = Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC, Cleary ML | title = Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy | journal = Nature | volume = 455 | issue = 7217 | pages = 1205–1209 | date = October 2008 | pmid = 18806775 | pmc = 4084721 | doi = 10.1038/nature07284 | bibcode = 2008Natur.455.1205W }}</ref> Supporting this claim, GSK-3 inhibitors have been shown to induce apoptosis in glioma and pancreatic cancer cells.<ref name="pmid18701488"/><ref name="pmid22201186">{{cite journal | vauthors = Marchand B, Tremblay I, Cagnol S, Boucher MJ | title = Inhibition of glycogen synthase kinase-3 activity triggers an apoptotic response in pancreatic cancer cells through JNK-dependent mechanisms | journal = Carcinogenesis | volume = 33 | issue = 3 | pages = 529–537 | date = March 2012 | pmid = 22201186 | doi = 10.1093/carcin/bgr309 | doi-access = free }}</ref> GSK-3 also seems to be responsible for NFκB aberrant activity in pediatric acute lymphoblastic leukemia and pancreatic cancer cells. In renal cancer cells, GSK-3 inhibitors induce cell cycle arrest, differentiation of the malignant cells, and autophagy. In contrast to the above neoplasms, high expression of inactive pGSK3β-S9 is found in skin, oral, and lung cancers, suggesting tumor suppressive effects of the enzyme in these cancers. In melanoma, the microRNA miR-769 inhibits GSK-3 activity during the tumor development process, also indicating tumor suppressive effects of GSK3.<ref name="Glibo_2021" />

GSK-3 inhibitors have also shown promise in the treatment of T2DM.<ref name="pmid19366350"/> Though GSK-3 activity under diabetic conditions can differ radically across different tissue types, studies have shown that introducing competitive inhibitors of GSK-3 can increase glucose tolerance in diabetic mice.<ref name="pmid16944320"/> GSK-3 inhibitors may also have therapeutic effects on [[hemorrhagic transformation]] after acute ischemic stroke.<ref name="pmid26671619">{{cite journal | vauthors = Wang W, Li M, Wang Y, Li Q, Deng G, Wan J, Yang Q, Chen Q, Wang J | display-authors = 6 | title = GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats | journal = Molecular Neurobiology | volume = 53 | issue = 10 | pages = 7028–7036 | date = December 2016 | pmid = 26671619 | pmc = 4909586 | doi = 10.1007/s12035-015-9607-2 }}</ref> GSK-3 can negatively regulate the insulin signaling pathway by inhibiting IRS1 via phosphorylation of serine-332,<ref name="pmid15574412" /> rendering the insulin receptor incapable of activating IRS1 and further initiating the canonical PI3K/Akt pathway. The role that inhibition of GSK-3 might play across its other signaling roles is not yet entirely understood.

GSK-3 inhibition also mediates an increase in the transcription of the transcription factor Tbet (Tbx21) and an inhibition of the transcription of the inhibitory co-receptor programmed cell death-1 (PD-1) on T-cells.<ref>{{cite journal | vauthors = Taylor A, Harker JA, Chanthong K, Stevenson PG, Zuniga EI, Rudd CE | title = Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8(+) Cytolytic T Cell Responses | journal = Immunity | volume = 44 | issue = 2 | pages = 274–286 | date = February 2016 | pmid = 26885856 | pmc = 4760122 | doi = 10.1016/j.immuni.2016.01.018 }}</ref>  GSK-3 inhibitors increased in vivo CD8(+) OT-I CTL function and the clearance of viral infections by murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 as well as anti-PD-1 in immunotherapy.