Selective loss of endogenous p21waf1/cip1 induction underlies the G1 checkpoint defect of monomeric p53 proteins
| Autor: | M, Tarunina, M, Grimaldi, E, Ruaro, M, Pavlenko, C, Schneider, J R, Jenkins |
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| Rok vydání: | 1996 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Transcriptional Activation Mice Inbred BALB C Osteosarcoma Binding Sites Base Sequence Microinjections Papillomavirus E7 Proteins Molecular Sequence Data G1 Phase Apoptosis DNA Oncogene Proteins Viral Fibroblasts Rats Mice Cell Transformation Neoplastic Genes ras Cyclins Consensus Sequence Animals Humans Tumor Suppressor Protein p53 Cell Division Cells Cultured |
| Zdroj: | Oncogene. 13(3) |
| ISSN: | 0950-9232 |
| Popis: | Wild-type p53 protein displays a spectrum of activities including the ability to suppress transformed cell growth to direct apoptotic cell death and to mediate G1 checkpoint in response to cellular DNA damage. Earlier work showed that a self-association defective p53 protein retained transformation suppressor activity in rat embryo fibroblast based assays, but that monomerisation of tumour mutant p53 proteins resulted in loss of dominant transforming activity. In order to acquire a more detailed understanding of the biological consequences attendant on disruption of p53:p53 association we have carried out a study of the wild-type-like activities that are retained by monomeric p53 proteins and which are associated with the suppression of transformation. Here we show that monomeric p53 proteins are G1 checkpoint defective. Although able to stimulate transcription via a p53 DNA binding motif from the p21waf1/cip1 gene promoter in episome based assays these p53 proteins are unable to transactive the chromosomal p21waf1/cip1 gene and are sensitive both to degeneracy of consensus binding site and to half site spacing. Monomeric p53 proteins fail to trigger apoptosis in a BRK cell line transformed with E7 and ras. However, they retain wild type transformation suppressor activity in BRK cell based transformation assays. Our results indicate that p21waf1/cip1 induction and all related p53 dependent G1 checkpoint activities are dispensable for the p53 directed suppression of transformed cell growth, and that such transformation suppression by monomeric p53 proteins may occur in the absence of an apoptotic response. |
| Databáze: | OpenAIRE |
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