BCL2L2 explained

Bcl-2-like protein 2 is a 193-amino acid protein that in humans is encoded by the BCL2L2 gene on chromosome 14 (band q11.2-q12).^{[1] [2] [3]} It was originally discovered by Leonie Gibson, Suzanne Cory and colleagues at the Walter and Eliza Hall Institute of Medical Research, who called it Bcl-w.^[4]

Function

This gene encodes a pro-survival (anti-apoptotic) member of the bcl-2 protein family, and is most similar to Bcl-xL. The proteins of this family form hetero- or homodimers and act as anti- and pro-apoptotic regulators. Expression of this gene in cells has been shown to contribute to reduced cell apoptosis under cytotoxic conditions. Studies of the related gene in mice indicated a role in the survival of NGF- and BDNF-dependent neurons. Mutation and knockout studies of the mouse gene demonstrated an essential role in adult spermatogenesis.^{[2] [5]}

Clinical significance

High levels of Bcl-w are seen in many cancers, including glioblastoma, colorectal cancer, non-small-cell lung carcinoma, and breast cancer. Breast cancer patients with metastasis have higher Bcl-w than breast cancer patients only having primary tumor. Elevated levels of Bcl-w has been shown to protect neurons from cell death induced by amyloid beta. Parkinson's disease patients with a mutant PARK2 gene have elevated Bcl-w. Bcl-w has been shown to contribute to cellular senescence.

Quercetin has been shown to inhibit the PI3K/AKT pathway leading to downregulation of Bcl-w.^[6]

Interactions

BCL2L2 has been shown to interact with:

• BCL2L11^{[7] [8]}
• BAD,^{[9] [10] [11]} and
• PPP1CA.^[12]

Further reading

• Nagase T, Seki N, Ishikawa K . Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain. . DNA Res. . 3 . 5 . 321–9, 341–54 . 1997 . 9039502 . 10.1093/dnares/3.5.321 . etal. free .
• O'Connor L, Strasser A, O'Reilly LA . Bim: a novel member of the Bcl-2 family that promotes apoptosis. . EMBO J. . 17 . 2 . 384–95 . 1998 . 9430630 . 10.1093/emboj/17.2.384 . 1170389 . etal.
• Ross AJ, Waymire KG, Moss JE . Testicular degeneration in Bclw-deficient mice. . Nat. Genet. . 18 . 3 . 251–6 . 1998 . 9500547 . 10.1038/ng0398-251 . 32843609 . etal.
• Hsu SY, Lin P, Hsueh AJ . BOD (Bcl-2-related ovarian death gene) is an ovarian BH3 domain-containing proapoptotic Bcl-2 protein capable of dimerization with diverse antiapoptotic Bcl-2 members. . Mol. Endocrinol. . 12 . 9 . 1432–40 . 1998 . 9731710 . 10.1210/mend.12.9.0166 . free .
• Middleton G, Wyatt S, Ninkina N, Davies AM . Reciprocal developmental changes in the roles of Bcl-w and Bcl-x(L) in regulating sensory neuron survival. . Development . 128 . 3 . 447–57 . 2001 . 10.1242/dev.128.3.447 . 11152643 .
• O'Reilly LA, Print C, Hausmann G . Tissue expression and subcellular localization of the pro-survival molecule Bcl-w. . Cell Death Differ. . 8 . 5 . 486–94 . 2001 . 11423909 . 10.1038/sj.cdd.4400835 . etal. free .
• Bae J, Hsu SY, Leo CP . Underphosphorylated BAD interacts with diverse antiapoptotic Bcl-2 family proteins to regulate apoptosis. . Apoptosis . 6 . 5 . 319–30 . 2001 . 11483855 . 10.1023/A:1011319901057 . 23119757 . etal.
• Puthalakath H, Villunger A, O'Reilly LA . Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. . Science . 293 . 5536 . 1829–32 . 2001 . 11546872 . 10.1126/science.1062257 . 2001Sci...293.1829P . 5638023 . etal.
• Ayllón V, Cayla X, García A . The anti-apoptotic molecules Bcl-xL and Bcl-w target protein phosphatase 1alpha to Bad. . Eur. J. Immunol. . 32 . 7 . 1847–55 . 2002 . 12115603 . 10.1002/1521-4141(200207)32:7<1847::AID-IMMU1847>3.0.CO;2-7 . etal. free .
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . etal. free .
• Denisov AY, Madiraju MS, Chen G . Solution structure of human BCL-w: modulation of ligand binding by the C-terminal helix. . J. Biol. Chem. . 278 . 23 . 21124–8 . 2003 . 12651847 . 10.1074/jbc.M301798200 . etal. free .
• Hinds MG, Lackmann M, Skea GL . The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity. . EMBO J. . 22 . 7 . 1497–507 . 2003 . 12660157 . 10.1093/emboj/cdg144 . 152889 . etal.
• Wilson-Annan J, O'Reilly LA, Crawford SA . Proapoptotic BH3-only proteins trigger membrane integration of prosurvival Bcl-w and neutralize its activity. . J. Cell Biol. . 162 . 5 . 877–87 . 2003 . 12952938 . 10.1083/jcb.200302144 . 2172834 . etal.
• Zhu X, Wang Y, Ogawa O . Neuroprotective properties of Bcl-w in Alzheimer disease. . J. Neurochem. . 89 . 5 . 1233–40 . 2004 . 15147516 . 10.1111/j.1471-4159.2004.02416.x . etal. free .
• Gerhard DS, Wagner L, Feingold EA . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . etal.
• Chen L, Willis SN, Wei A . Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. . Mol. Cell . 17 . 3 . 393–403 . 2005 . 15694340 . 10.1016/j.molcel.2004.12.030 . etal. free .
• Kimura K, Wakamatsu A, Suzuki Y . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. . Genome Res. . 16 . 1 . 55–65 . 2006 . 16344560 . 10.1101/gr.4039406 . 1356129 . etal.
• Denisov AY, Chen G, Sprules T . Structural model of the BCL-w-BID peptide complex and its interactions with phospholipid micelles. . Biochemistry . 45 . 7 . 2250–6 . 2006 . 16475813 . 10.1021/bi052332s . etal.
• Certo M, Del Gaizo Moore V, Nishino M . Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. . Cancer Cell . 9 . 5 . 351–65 . 2006 . 16697956 . 10.1016/j.ccr.2006.03.027 . etal. free .

Notes and References

1. Gibson L, Holmgreen SP, Huang DC, Bernard O, Copeland NG, Jenkins NA, Sutherland GR, Baker E, Adams JM, Cory S . Grant Robert Sutherland . bcl-w, a novel member of the bcl-2 family, promotes cell survival . Oncogene . 13 . 4 . 665–75 . October 1996 . 8761287 .
2. Web site: Entrez Gene: BCL2L2 BCL2-like 2.
3. Hartman ML, Czyz M . BCL-w: apoptotic and non-apoptotic role in health and disease . Cell Death & Disease. 11 . 4 . 2260 . 2020 . 10.1038/s41419-020-2417-0 . 7174325 . 32317622.
4. Gibson L, Holmgreen SP, Huang DC . bcl-w, a novel member of the bcl-2 family, promotes cell survival. . Oncogene . 13 . 4 . 665–75 . 1996 . 8761287 . etal.
5. 10.1146/annurev-cancerbio-030419-033510. free. Toward Targeting Antiapoptotic MCL-1 for Cancer Therapy. 2020. Kelly. Gemma L.. Strasser. Andreas. Annual Review of Cancer Biology. 4. 299–313. 11343/252362. free.
6. Paez-Ribes M, González-Gualda E, Doherty GJ, Muñoz-Espín D . Targeting senescent cells in translational medicine . . 11 . 12 . e10234 . 2019 . 10.15252/emmm.201810234 . 6895604 . 31746100.
7. Hsu SY, Lin P, Hsueh AJ . BOD (Bcl-2-related ovarian death gene) is an ovarian BH3 domain-containing proapoptotic Bcl-2 protein capable of dimerization with diverse antiapoptotic Bcl-2 members . Mol. Endocrinol. . 12 . 9 . 1432–40 . September 1998 . 9731710 . 10.1210/mend.12.9.0166 . free .
8. January 1998 . O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC . Bim: a novel member of the Bcl-2 family that promotes apoptosis . EMBO J. . 17 . 2 . 384–95 . 9430630 . 1170389 . 10.1093/emboj/17.2.384.
9. February 2005 . Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC . Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function . Mol. Cell . 17 . 3 . 393–403 . 15694340 . 10.1016/j.molcel.2004.12.030. free .
10. October 2001 . Bae J, Hsu SY, Leo CP, Zell K, Hsueh AJ . Underphosphorylated BAD interacts with diverse antiapoptotic Bcl-2 family proteins to regulate apoptosis . Apoptosis . 6 . 5 . 319–30 . 11483855 . 10.1023/A:1011319901057. 23119757 .
11. June 1999 . Holmgreen SP, Huang DC, Adams JM, Cory S . Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members . Cell Death Differ. . 6 . 6 . 525–32 . 10381646 . 10.1038/sj.cdd.4400519. free .
12. July 2002 . Ayllón V, Cayla X, García A, Fleischer A, Rebollo A . The anti-apoptotic molecules Bcl-xL and Bcl-w target protein phosphatase 1alpha to Bad . Eur. J. Immunol. . 32 . 7 . 1847–55 . 12115603 . 10.1002/1521-4141(200207)32:7<1847::AID-IMMU1847>3.0.CO;2-7. free .