Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant.
The p53 tumor-suppressor gene product is frequently inactivated in malignancies by point mutation. Although most tumor-derived p53 mutants show loss of sequence specific transcriptional activation, some mutants have been identified which retain this activity. One such mutant, p53175P, is defective for the suppression of transformation in rodent cells, despite retaining the ability to suppress the growth of p53-null human cells. We now demonstrate that p53175P can induce a cell-cycle arrest in appropriate cell types but shows loss of apoptotic function. Our results therefore support a direct role of p53 transcriptional activation in mediating a cell-cycle arrest and demonstrate that such activity is not sufficient for the full apoptotic response. These data suggest that either p53 can induce apoptosis through a transcriptionally independent mechanism, a function lost by p53175P, or that this mutant has specifically lost the ability to activate genes which contribute to cell death, despite activation of genes responsible for the G1 arrest. This dissociation of the cell-cycle arrest and apoptotic activities of p53 indicates that inactivation of p53 apoptotic function without concomitant loss of growth inhibition can suffice to relieve p53-dependent tumor-suppression in vivo and thereby contribute to tumor development.
Rowan
S
S
ABL Basic Research Program, NCI-FCRDC, Frederick, Maryland 21702, USA.
Ludwig
R L
RL
Haupt
Y
Y
Bates
S
S
Lu
X
X
Oren
M
M
Vousden
K H
KH
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000502:physiology; D050725:Papillomavirus E7 Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D051028:bcl-2-Associated X Protein
D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; 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; C059731:oncogene protein E7, Human papillomavirus type 16; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)