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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Willis, Simon N. Chen, Lin Dewson, Grant Wei, Andrew Naik, Edwina Fletcher, Jamie I. Adams, Jerry M. Huang, David C. S. |
| Description | Country affiliation: Australia Author Affiliation: Willis SN ( The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.) |
| Abstract | Commitment of cells to apoptosis is governed largely by the interaction between members of the Bcl-2 protein family. Its three subfamilies have distinct roles: The BH3-only proteins trigger apoptosis by binding via their BH3 domain to prosurvival relatives, while the proapoptotic Bax and Bak have an essential downstream role involving permeabilization of organellar membranes and induction of caspase activation. We have investigated the regulation of Bak and find that, in healthy cells, Bak associates with Mcl-1 and Bcl-x(L) but surprisingly not Bcl-2, Bcl-w, or A1. These interactions require the Bak BH3 domain, which is also necessary for Bak dimerization and killing activity. When cytotoxic signals activate BH3-only proteins that can engage both Mcl-1 and Bcl-x(L) (such as Noxa plus Bad), Bak is displaced and induces cell death. Accordingly, the BH3-only protein Noxa could bind to Mcl-1, displace Bak, and promote Mcl-1 degradation, but Bak-mediated cell death also required neutralization of Bcl-x(L) by other BH3-only proteins. The results indicate that Bak is held in check solely by Mcl-1 and Bcl-x(L) and induces apoptosis only if freed from both. The finding that different prosurvival proteins have selective roles has notable implications for the design of anti-cancer drugs that target the Bcl-2 family. |
| File Format | HTM / HTML |
| ISSN | 08909369 |
| e-ISSN | 15495477 |
| Journal | Genes & Development |
| Issue Number | 11 |
| Volume Number | 19 |
| Language | English |
| Publisher | Cold Spring Harbor Laboratory Press |
| Publisher Date | 2005-06-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Discipline Molecular Discipline Biology__semicolon__developmental Discipline Biology__semicolon__genetics__semicolon__cell Discipline Biology Apoptosis Physiology Membrane Proteins Neoplasm Proteins Proto-oncogene Proteins C-bcl-2 Amino Acid Sequence Radiation Effects Hela Cells Chemistry Molecular Sequence Data Myeloid Cell Leukemia Sequence 1 Protein Ultraviolet Rays Bcl-2 Homologous Antagonist-killer Protein Bcl-x Protein Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Research Support, U.s. Gov't, P.h.s. |
| Content Type | Text |
| Resource Type | Article |
| Subject | Genetics Developmental Biology |
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