c-Myc Augments Gamma Irradiation-Induced Apoptosis by Suppressing Bcl-X_L

Abstract

Alterations in MYC and p53 are hallmarks of cancer. p53 coordinates the response to gamma irradiation (γ-IR) by either triggering apoptosis or cell cycle arrest. c-Myc activates the p53 apoptotic checkpoint, and thus tumors overexpressing MYC often harbor p53 mutations. Nonetheless, many of these cancers are responsive to therapy, suggesting that Myc may sensitize cells to γ-IR independent of p53. In mouse embryo fibroblasts (MEFs) and in Eμ-myc transgenic B cells in vivo, c-Myc acts in synergy with γ-IR to trigger apoptosis, but alone, when cultured in growth medium, it does not induce a DNA damage response. Surprisingly, c-Myc also sensitizes p53-deficient MEFs to γ-IR-induced apoptosis. In normal cells, and in precancerous B cells of Eμ-myc transgenic mice, this apoptotic response is associated with the suppression of the antiapoptotic regulators Bcl-2 and Bcl-X_L and with the concomitant induction of Puma, a proapoptotic BH3-only protein. However, in p53-null MEFs only Bcl-X_L expression was suppressed, suggesting levels of Bcl-X_L regulate the response to γ-IR. Indeed, Bcl-X_L overexpression blocked this apoptotic response, whereas bcl-X-deficient MEFs were inherently and selectively sensitive to γ-IR-induced apoptosis. Therefore, MYC may sensitize tumor cells to DNA damage by suppressing Bcl-X.

ACKNOWLEDGMENTS

We are grateful for the outstanding technical assistance of Elsie L. White, Chunying Yang, Sara Norton, Rob Jeffers, and Kristen Rothhammer. We also thank the staff of our Animal Resources Center for care and monitoring of animals and members of the Flow Cytometry facility. We thank Martine Roussel and Frederique Zindy for discussion. Finally, we also thank Craig Thompson and David Woo for providing bcl-X^+/− and bcl-2^−/− mice.

This work was supported in part by grants DK44158 and CA76379 (J.L.C.), Cancer Center CORE grant CA21765, and by the American Lebanese Syrian Associated Charities. U.B.K. is a fellow of the Deutsche Forschungsgemeinschaff (grant KE 222/5-1).