Induction of apoptosis in HeLa cells by trans-activation-deficient p53.
The p53 tumor suppressor protein is a transcriptional activator, which can mediate apoptotic cell death in a variety of cell types. To determine whether sequence-specific trans-activation is a prerequisite for the induction of apoptosis by p53, the apoptotic effects of various p53 deletion mutants were monitored in an assay based on the transient transfection of HeLa cells. A truncated protein (p53dl214), containing only the first 214 amino-terminal residues of murine p53, induced extensive apoptosis, albeit at a slower rate than trans-activation-competent wild-type p53. p53dl214 also suppressed the transformation of rat fibroblasts by several oncogene combinations and particularly by myc plus ras and HPV E7 plus ras. p53dl214 lacks a major portion of the DNA-binding domain and cannot activate p53-responsive promoters. Moreover, a human p53 protein carrying mutations in residues 22 and 23 also triggered HeLa cell apoptosis, despite failing to induce significant activation of relevant p53 target promoters. These data suggest the existence of two p53-dependent apoptotic pathways--one requiring activation of specific target genes, and the other independent of sequence-specific trans-activation. The latter pathway may actually be totally uncoupled from the binding of p53 to its consensus DNA sites. The relative contribution of trans-activation-independent apoptosis to tumor suppression by p53 may be dictated by the specific genetic lesions present in the particular tumor.
Haupt
Y
Y
Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Rowan
S
S
Shaulian
E
E
Vousden
K H
KH
Oren
M
M
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D009857:Oncogenes; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000235:genetics; D017384:Sequence Deletion; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D015375:Receptors, Interleukin-2; D016159:Tumor Suppressor Protein p53; D004247:DNA