“TRAIL”的意思、由来-开放百科全书

In the field of cell biology, TNF-related apoptosis-inducing ligand (TRAIL), is a protein functioning as a ligand that induces the process of cell death called apoptosis.^[1]^[2]

TRAIL is a cytokine that is produced and secreted by most normal tissue cells. It causes apoptosis primarily in tumor cells,^[3] by binding to certain death receptors. TRAIL and its receptors have been used as the targets of several anti-cancer therapeutics since the mid-1990s, such as Mapatumumab. However, as of 2013, these have not shown significant survival benefit.^[3] TRAIL has also been implicated as a pathogenic or protective factor in various pulmonary diseases, particularly pulmonary arterial hypertension.^[4]

TRAIL has also been designated CD253 (cluster of differentiation 253) and TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10).^[5]

Gene

In humans, the gene that encodes TRAIL is located at chromosome 3q26, which is not close to other TNF family members.^[1] The genomic structure of the TRAIL gene spans approximately 20 kb and is composed of five exonic segments 222, 138, 42, 106, and 1245 nucleotides and four introns of approximately 8.2, 3.2, 2.3 and 2.3 kb.

The TRAIL gene lacks TATA and CAAT boxes and the promotor region contains putative response elements for transcription factors GATA, AP-1, C/EBP, SP-1, OCT-1, AP3, PEA3, CF-1, and ISRE.{{citation needed|date=February 2016}}

The TRAIL gene as a drug target

Structure

TRAIL shows homology to other members of the tumor necrosis factor superfamily. It is composed of 281 amino acids and has characteristics of a type II transmembrane protein (i.e. no leader sequence and an internal transmembrane domain). The N-terminal cytoplasmic domain is not conserved across family members, however, the C-terminal extracellular domain is conserved and can be proteolytically cleaved from the cell surface. TRAIL forms a homotrimer that binds three receptor molecules.

Function

TRAIL binds to the death receptors DR4 (TRAIL-RI) and DR5 (TRAIL-RII). The process of apoptosis is caspase-8-dependent. Caspase-8 activates downstream effector caspases including procaspase-3, -6, and -7, leading to activation of specific kinases.^[7] TRAIL also binds the receptors DcR1 and DcR2, which do not contain a cytoplasmic domain (DcR1) or contain a truncated death domain (DcR2). DcR1 functions as a TRAIL-neutralizing decoy-receptor. The cytoplasmic domain of DcR2 is functional and activates NFkappaB.

In cells expressing DcR2, TRAIL binding therefore activates NFkappaB, leading to transcription of genes known to antagonize the death signaling pathway and/or to promote inflammation. Application of engineered ligands that have variable affinity for different death (DR4 and DR5) and decoy receptors (DCR1 and DCR2) may allow selective targeting of cancer cells by controlling activation of Type 1/Type 2 pathways of cell death and single cell fluctuations.

The TRAIL receptors as a drug target

In clinical trials only a small proportion of cancer patients responded to various drugs that targeted TRAIL death receptors. Many cancer cell lines develop resistance to TRAIL and limits the efficacy of TRAIL-based therapies.^[8]

Interactions

See also

References

1. ^¹{{cite journal | vauthors = Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA | title = Identification and characterization of a new member of the TNF family that induces apoptosis | journal = Immunity | volume = 3 | issue = 6 | pages = 673–82 |date=December 1995 | pmid = 8777713 | doi = 10.1016/1074-7613(95)90057-8| url = }}
2. ^{{cite journal | vauthors = Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A | title = Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family | journal = J. Biol. Chem. | volume = 271 | issue = 22 | pages = 12687–90 |date=May 1996 | pmid = 8663110 | doi = 10.1074/jbc.271.22.12687| url = http://www.jbc.org/cgi/content/full/271/22/12687 }}
3. ^¹{{cite journal | author = Cormier Z | title = Small-molecule drug drives cancer cells to suicide | journal = Nature |date=February 2013 | volume = 494 | doi = 10.1038/nature.2013.12385 }}
4. ^{{Cite journal|last=Braithwaite|first=Adam T.|last2=Marriott|first2=Helen M.|last3=Lawrie|first3=Allan|date=2018|title=Divergent Roles for TRAIL in Lung Diseases|journal=Frontiers in Medicine|language=English|volume=5|doi=10.3389/fmed.2018.00212|pmid=30101145|issn=2296-858X}}
5. ^¹{{cite web|title=TNFSF10|work=NCBI Gene|date=|url=https://www.ncbi.nlm.nih.gov/gene/8743}}
6. ^ONC201: Stressing tumors to death. Feb 2016
7. ^{{cite journal | vauthors = Song JJ, Lee YJ | title = Differential cleavage of Mst1 by caspase-7/-3 is responsible for TRAIL-induced activation of the MAPK superfamily | journal = Cell. Signal. | volume = 20 | issue = 5 | pages = 892–906 |date=May 2008 | pmid = 18276109 | pmc = 2483832 | doi = 10.1016/j.cellsig.2008.01.001 | url = }}
8. ^{{cite journal |url=http://www.nature.com/onc/journal/v32/n11/full/onc2012164a.html |journal=Oncogene |pages=1341–1350 |volume=32 |issue=11 |date=14 March 2013 |doi=10.1038/onc.2012.164 |pmid=22580613 |title=On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics |last1=Dimberg |first1=L Y |last2=Anderson |first2=C K |last3=Camidge |first3=R |last4=Behbakht |first4=K |last5=Thorburn |first5=A |last6=Ford |first6=H L |pmc=4502956 }}
9. ^{{cite journal | vauthors = Kaptein A, Jansen M, Dilaver G, Kitson J, Dash L, Wang E, Owen MJ, Bodmer JL, Tschopp J, Farrow SN | title = Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3) | journal = FEBS Lett. | volume = 485 | issue = 2–3 | pages = 135–41 |date=November 2000 | pmid = 11094155 | doi = 10.1016/S0014-5793(00)02219-5 }}
10. ^{{cite journal | vauthors = Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG, Rauch CT | title = TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL | journal = EMBO J. | volume = 16 | issue = 17 | pages = 5386–97 |date=September 1997 | pmid = 9311998 | pmc = 1170170 | doi = 10.1093/emboj/16.17.5386 }}
11. ^{{cite journal | vauthors = Hymowitz SG, Christinger HW, Fuh G, Ultsch M, O'Connell M, Kelley RF, Ashkenazi A, de Vos AM | title = Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5 | journal = Mol. Cell | volume = 4 | issue = 4 | pages = 563–71 |date=October 1999 | pmid = 10549288 | doi = 10.1016/S1097-2765(00)80207-5 }}