TY - JOUR
T1 - c-Myc augments gamma irradiation-induced apoptosis by suppressing Bcl-XL
AU - Maclean, Kirsteen H
AU - Keller, Ulrich B
AU - Rodriguez-Galindo, Carlos
AU - Nilsson, Jonas A
AU - Cleveland, John L
PY - 2003/10
Y1 - 2003/10
N2 - Alterations in MYC and p53 are hallmarks of cancer. p53 coordinates the response to gamma irradiation (gamma-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 gamma-IR independent of p53. In mouse embryo fibroblasts (MEFs) and in E micro -myc transgenic B cells in vivo, c-Myc acts in synergy with gamma-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 gamma-IR-induced apoptosis. In normal cells, and in precancerous B cells of E micro -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 gamma-IR. Indeed, Bcl-X(L) overexpression blocked this apoptotic response, whereas bcl-X-deficient MEFs were inherently and selectively sensitive to gamma-IR-induced apoptosis. Therefore, MYC may sensitize tumor cells to DNA damage by suppressing Bcl-X.
AB - Alterations in MYC and p53 are hallmarks of cancer. p53 coordinates the response to gamma irradiation (gamma-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 gamma-IR independent of p53. In mouse embryo fibroblasts (MEFs) and in E micro -myc transgenic B cells in vivo, c-Myc acts in synergy with gamma-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 gamma-IR-induced apoptosis. In normal cells, and in precancerous B cells of E micro -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 gamma-IR. Indeed, Bcl-X(L) overexpression blocked this apoptotic response, whereas bcl-X-deficient MEFs were inherently and selectively sensitive to gamma-IR-induced apoptosis. Therefore, MYC may sensitize tumor cells to DNA damage by suppressing Bcl-X.
KW - Animals
KW - Apoptosis
KW - Apoptosis Regulatory Proteins
KW - Blotting, Northern
KW - Cell Survival
KW - Cells, Cultured
KW - Comet Assay
KW - DNA Damage
KW - DNA, Complementary/metabolism
KW - Fibroblasts/metabolism
KW - Gamma Rays
KW - Green Fluorescent Proteins
KW - Immunoblotting
KW - Luminescent Proteins/metabolism
KW - Mice
KW - Mice, Transgenic
KW - Microscopy, Confocal
KW - Mutation
KW - Neoplasms/metabolism
KW - Proteins/metabolism
KW - Proto-Oncogene Proteins
KW - Proto-Oncogene Proteins c-bcl-2/metabolism
KW - Proto-Oncogene Proteins c-myc/metabolism
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Time Factors
KW - Tumor Suppressor Protein p53/metabolism
KW - bcl-X Protein
U2 - 10.1128/MCB.23.20.7256-7270.2003
DO - 10.1128/MCB.23.20.7256-7270.2003
M3 - Article
C2 - 14517295
SN - 0270-7306
VL - 23
SP - 7256
EP - 7270
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 20
ER -