PUMA Dissociates Bax and Bcl-XL to Induce Apoptosis in Colon Cancer Cells
| Autor: | Peng Wang, Alexander Bank, Lin Zhang, Lihua Ming, Jian Yu |
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| Rok vydání: | 2006 |
| Předmět: |
Blotting
Western Molecular Sequence Data Mutant bcl-X Protein Bcl-xL Binding Competitive Biochemistry chemistry.chemical_compound RNA interference Proto-Oncogene Proteins hemic and lymphatic diseases Puma Humans Amino Acid Sequence RNA Small Interfering Molecular Biology bcl-2-Associated X Protein Gene knockdown Base Sequence biology Cell Biology biology.organism_classification In vitro Cell biology chemistry Apoptosis Colonic Neoplasms biology.protein biological phenomena cell phenomena and immunity Apoptosis Regulatory Proteins DNA |
| Zdroj: | Journal of Biological Chemistry. 281:16034-16042 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m513587200 |
| Popis: | PUMA is a BH3-only Bcl-2 family protein that plays an essential role in DNA damage-induced apoptosis. PUMA interacts with anti-apoptotic Bcl-2 and Bcl-X(L) and is dependent on Bax to induce apoptosis. In this study, we investigated how the interactions of PUMA with the antiapoptotic proteins coordinate with Bax to initiate apoptosis in HCT116 colon cancer cells. We found that Bcl-X(L) was most effective among several antiapoptotic proteins in suppressing PUMA-induced apoptosis and PUMA-dependent apoptosis induced by the DNA-damaging agent adriamycin. Mutant Bcl-X(L) that cannot interact with Bax was unable to protect cells from PUMA-mediated apoptosis. Knockdown of Bcl-X(L) by RNA interference significantly enhanced PUMA-mediated apoptosis in HCT116 cells but not in PUMA-knockout cells. Furthermore, Bax was found to be dissociated preferentially from Bcl-X(L) in HCT116 cells but not in the PUMA-knockout cells, in response to PUMA induction and adriamycin treatment. PUMA inhibited the association of Bax and Bcl-X(L) in vitro by directly binding to Bcl-X(L) through its BH3 domain. Finally, we found that wild-type Bax, but not mutant Bax deficient in either multimerization or mitochondrial localization, was able to restore PUMA-induced apoptosis in the BAX-knockout cells. Together, these results indicate that PUMA initiates apoptosis in part by dissociating Bax and Bcl-X(L), thereby promoting Bax multimerization and mitochondrial translocation. |
| Databáze: | OpenAIRE |
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