Table 1.
Mechanisms of Antiapoptotic Bcl-2 Family Member Dysregulation in Cancer
| Bcl-2 family member | Overexpressed in | Genomic alterations | miRNA loss | E3 ubiquitin ligase loss | Other mechanisms |
|---|---|---|---|---|---|
| Bcl-2 | Lymphoid malignancies [115–117] and melanoma [224] as well as small cell lung [21, 225], breast [226], prostate [227], colorectal [228] and bladder cancers [229]. | t(14;18) chromosomal translocation in lymphomas [17, 93, 94] | Loss of miR-15a and miR-16 in CLL [121] Loss of miR- 195, miR-24- 2, miR-365-2 and miR-204 in breast, lung and colon cancer [230, 231] | Loss of INrf2 [124] | |
| Bcl-xL | Hormone-refractory breast cancer [233] prostate cancer [232] and mesenchymal | Gene amplificatio n, often in concert with c-Myc, in multiple solid tumors [18] | Decrease miR-let7c in hepatocellular and lung cancers [234, 235] as well as AML [236] Decreased miR-491-5P in pancreatic [237], colorectal [238], and ovarian cancer [237]. |
Loss of phosphoglycer ate mutase 5, which is required for binding to the E3 ligase INrf2 [124] | Stat5 activation by Bcr/abl in CML [239] |
| Mcl-1 | Relapsed acute leukemia [120], CLL [240], multiple myeloma [241–243] as well as breast [244], ovarian [245], colorectal [246], gastric [247], hepatocellular [248], and non-small cell lung cancers [18]. | Gene amplificatio n in multiple solid tumors [18] | Loss of miR- 29 in many solid tumors [249], miR- 125b in hepatocellular carcinoma [250, 251] or miR-133b in lung cancer [252] | Increased expression of the deubiquitinase USP9X in FL, DLBCL and multiple myeloma [250] Mutation or loss of the E3 ubiquitin ligase FBW7 in a variety of cancers [253, 254] | NFκB- mediated transcription, e.g., in large granular lymphocytic leukemia [255] |
| Bcl-w | Gastric [256, 257] and colorectal cancers [258] as well as glioblastomamultifor me [259, 260]. | Gene amplificatio n in CML, ovarian and colorectal cancers [261, 262] | Downregulati on miR-125b [251], miR- 335 [263, 264], miR- 497 [265], miR-203 [266] or miR- 122 [267] | Not known | Enhanced promoter activity by β-catenin/ TGF4 signaling in colorectal cancer [268]. |
| BFL1 | ALL, CLL and DLBL [269-272]. | Not known | Not known | Regulated by ubiquitination. No E3 ligase has been identified (\[273, 274]. | Transcription al activation by NFκB [275], e.g., downstream of constitutive PI3K or ERK activation [276, 277] that occurs in many solid tumors. |
| Bcl-B | DLBL and breast, prostatic, gastric, colorectal, and small cell lung cancers [278]. High level associates with poor prognosis. | Not known | Not reported | Ubiquitinated protein. No E3 ligase has been identified [279]. | Not known |