Editing Apoptosis (section)

==== TNF pathway ====
[[TNF-alpha]] is a [[cytokine]] produced mainly by activated [[macrophage]]s, and is the major extrinsic mediator of apoptosis. Most cells in the human body have two receptors for TNF-alpha: [[TNFR1]] and [[TNFR2]]. The binding of TNF-alpha to TNFR1 has been shown to initiate the pathway that leads to caspase activation via the intermediate membrane proteins TNF receptor-associated death domain ([[TRADD]]) and Fas-associated death domain protein ([[FADD]]). [[cIAP1]]/2 can inhibit TNF-α signaling by binding to [[TRAF2]]. [[CFLAR|FLIP]] inhibits the activation of caspase-8.<ref name="tnfr1">{{cite journal | vauthors = Chen G, Goeddel DV | title = TNF-R1 signaling: a beautiful pathway | journal = Science | volume = 296 | issue = 5573 | pages = 1634–1635 | date = May 2002 | pmid = 12040173 | doi = 10.1126/science.1071924 | s2cid = 25321662 | bibcode = 2002Sci...296.1634C }}</ref> Binding of this receptor can also indirectly lead to the activation of [[transcription factor]]s involved in cell survival and inflammatory responses.<ref name="tfnpathway">{{cite journal| vauthors=Goeddel, DV| title=Connection Map for Tumor Necrosis Factor Pathway| journal=[[Science Signaling|Science's STKE]]| url=http://stke.sciencemag.org/cgi/cm/CMP_7107| doi=10.1126/stke.3822007tw132| volume=2007| issue=382| pages=tw132| year=2007| s2cid=85404086| access-date=2004-01-01| archive-date=2009-07-10| archive-url=https://web.archive.org/web/20090710024231/http://stke.sciencemag.org/cgi/cm/CMP_7107| url-status=dead| url-access=subscription}}</ref> However, signalling through TNFR1 might also induce apoptosis in a caspase-independent manner.<ref name="LAPFapoptosis">{{cite journal | vauthors = Chen W, Li N, Chen T, Han Y, Li C, Wang Y, He W, Zhang L, Wan T, Cao X | display-authors = 6 | title = The lysosome-associated apoptosis-inducing protein containing the pleckstrin homology (PH) and FYVE domains (LAPF), representative of a novel family of PH and FYVE domain-containing proteins, induces caspase-independent apoptosis via the lysosomal-mitochondrial pathway | journal = The Journal of Biological Chemistry | volume = 280 | issue = 49 | pages = 40985–40995 | date = December 2005 | pmid = 16188880 | doi = 10.1074/jbc.M502190200 | doi-access = free }}{{Retracted|doi=10.1016/j.jbc.2021.100764|http://retractionwatch.com/?s=%22Xuetao+Cao%22 ''Retraction Watch''|intentional=yes}}</ref>{{better source needed|date=October 2024}} The link between TNF-alpha and apoptosis shows why an abnormal production of TNF-alpha plays a fundamental role in several human diseases, especially in [[autoimmune disease]]s. The [[TNF receptor superfamily|TNF-alpha receptor superfamily]] also includes death receptors (DRs), such as [[Death receptor 4|DR4]] and [[Death receptor 5|DR5]]. These receptors bind to the protein [[TRAIL]] and mediate apoptosis. Apoptosis is known to be one of the primary mechanisms of targeted cancer therapy.<ref>{{cite journal | vauthors = Gerl R, Vaux DL | title = Apoptosis in the development and treatment of cancer | journal = Carcinogenesis | volume = 26 | issue = 2 | pages = 263–270 | date = February 2005 | pmid = 15375012 | doi = 10.1093/carcin/bgh283 | doi-access = free }}</ref> Luminescent iridium complex-peptide hybrids (IPHs) have recently been designed, which mimic TRAIL and bind to death receptors on cancer cells, thereby inducing their apoptosis.<ref>{{cite journal | vauthors = Masum AA, Yokoi K, Hisamatsu Y, Naito K, Shashni B, Aoki S | title = Design and synthesis of a luminescent iridium complex-peptide hybrid (IPH) that detects cancer cells and induces their apoptosis | journal = Bioorganic & Medicinal Chemistry | volume = 26 | issue = 17 | pages = 4804–4816 | date = September 2018 | pmid = 30177492 | doi = 10.1016/j.bmc.2018.08.016 | s2cid = 52149418 }}</ref>