P53 is necessary for the apoptotic response mediated by a transient increase of Ras activity.
The tumor suppressor p53 eliminates cancer-prone cells via multiple mechanisms, including apoptosis. Ras elicits apoptosis in cells after protein kinase C (PKC) downregulation. However, the role of p53 in Ras-mediated apoptosis has not been fully investigated. Here, we demonstrate that mouse fibroblasts that express wild-type p53 are more susceptible to apoptosis elicited by PKC inhibition if Ras is transiently expressed or upregulated as opposed to stably expressed. In the latter case, p53 is frequently mutated. Transiently increased Ras activity induces Bax, and PKC inhibition augments this induction. Overexpression of E6 inactivates p53 and thereby suppresses both Bax induction and apoptosis. In contrast, Bax is not induced in stable ras transfectants, regardless of PKC inhibition. The data suggest that short- and long-term activation of Ras use a different mechanism(s) to initiate apoptosis. The status of p53 may contribute to such differences.
Ma
Peihong
P
Cancer Research Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Magut
Maureen
M
Chen
XinBin
X
Chen
Chang-Yan
CY
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D005347:Fibroblasts; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D009154:Mutation; D016376:Oligonucleotides, Antisense; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D011493:Protein Kinase C; D016283:Proto-Oncogene Proteins p21(ras)