Anti-apoptotic activity of p53 maps to the COOH-terminal domain and is retained in a highly oncogenic natural mutant.
The tumour suppressor p53 plays a complex role in the regulation of apoptosis. High levels of wild type p53 potentiate the apoptotic response, while physiological range, low levels of the protein have an anti-apoptotic activity in serum starved immortalized fibroblasts. Here we report that primary fibroblast-like cells that show normal growth control are also efficiently protected from apoptosis by the endogenous p53 activity. The capacity to inhibit apoptosis is not restricted to the wild type protein: the R-->H175 p53 mutant fully retains the anti-apoptotic activity of the wild type p53, providing a possible explanation for its high oncogenicity. Using a series of point and deletion mutants of p53 under the control of tetracycline-regulated promoter we show that certain mutants, like the wild type, protect cells at low levels but lead to apoptosis when overexpressed. This latter effect is lost upon deletion of a proline-rich domain in the NH2 part of the protein. The anti-apoptotic activity can be mapped to the extreme carboxy-terminal part of the protein and is therefore independent of other well characterized p53 activities. Our results add a new level of complexity to the network of interactions mediated by p53 in normal physiology and pathology.
Lassus
P
P
Institut de Génétique Moléculaire, CNRS UMR 5535, 1919 route de Mende, 34293 Montpellier Cedex 5, France.
Bertrand
C
C
Zugasti
O
O
Chambon
J P
JP
Soussi
T
T
Mathieu-Mahul
D
D
Hibner
U
U
D000818:Animals; D017209:Apoptosis; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016895:Culture Media, Serum-Free; D004252:DNA Mutational Analysis; D016158:Genes, p53; D008954:Models, Biological; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016895:Culture Media, Serum-Free; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53