| First Author | Dehan E | Year | 2009 |
| Journal | Mol Cell | Volume | 33 |
| Issue | 1 | Pages | 109-16 |
| PubMed ID | 19150432 | Mgi Jnum | J:146160 |
| Mgi Id | MGI:3836845 | Doi | 10.1016/j.molcel.2008.12.020 |
| Citation | Dehan E, et al. (2009) betaTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis. Mol Cell 33(1):109-16 |
| abstractText | The BimEL tumor suppressor is a potent proapoptotic BH3-only protein. We found that, in response to survival signals, BimEL was rapidly phosphorylated on three serine residues in a conserved degron, facilitating binding and degradation via the F box protein betaTrCP. Phosphorylation of the BimEL degron was executed by Rsk1/2 and promoted by the Erk1/2-mediated phosphorylation of BimEL on Ser69. Compared to wild-type BimEL, a BimEL phosphorylation mutant unable to bind betaTrCP was stabilized and consequently potent at inducing apoptosis by the intrinsic mitochondrial pathway. Moreover, although non-small cell lung cancer (NSCLC) cells often become resistant to gefitinib (a clinically relevant tyrosine kinase inhibitor that induces apoptosis through BimEL), silencing of either betaTrCP or Rsk1/2 resulted in BimEL-mediated apoptosis of both gefitinib-sensitive and gefitinib-insensitive NSCLC cells. Our findings reveal that betaTrCP promotes cell survival in cooperation with the ERK-RSK pathway by targeting BimEL for degradation. |
