The tumour supressor protein p53 plays a key role in the cell's decision to arrest the cell cycle or undergo apoptosis following a genotoxic insult. p53 is stabilized and activated after DNA damage, however the cascade of events signalling from DNA lesions to p53 stabilization and activation is still controversial. Poly (ADPribosylation) of dierent nuclear acceptors by PARP-1 is an early event when a single strand DNA lesion is produced. We present here evidences that interplay between PARP-1 and p53 is dependent on the type of damage induced to DNA. Primary mouse embryonic ®broblasts derived from parp-17/7 mice exhibited decreased p53 accumulation and activation following girradiation compared to parp-1 pro®cient cells. On the other hand, treatment with the single alkylating agent 2'-methyl-2'-nitrose-urea (MNU), resulted in the rapid and sustained accumulation and activation of p53 in parp-1-de®cient cells, while very little accumulation was observed in parp-1+/+ cells. After IR, the turnover of the p53 inhibitory protein MDM-2 is perturbed and the level of phosphorylation of p53 at serine-15 is blunted in parp-17/7 cells. PARP-1 is determinant in the cytotoxic response to alkylating agents but only partially contributes to radiation-induced cell killing, as determined by colony forming assay. Altogether, these results suggest that PARP-1 participates in the p53 response following irradiation, resides upstream of p53 and indirectly modulates the level of phosphorylation of key substrates in this pathway while treatment with MNU results in an enhanced p53-mediated response in parp-1-null cells.
Poly (ADP-ribose) polymerase-1 (PARP-1)-deficient mice are protected against septic shock, type I diabetes, stroke and inflammation. It is now accepted that inflammation and related events, such as activation of NF-jB, are key components in the initiation and progression of epithelial cancer and in particular in the neoplastic transformation of keratinocytes and skin carcinogenesis. Here, we report that PARP-1-deficient mice display a strikingly reduced susceptibility to skin carcinogenesis. In parp-1 À/À mice, development of papilloma-like premalignant lesions induced with DMBA and TPA, is strongly delayed and the final number of tumorbearing mice and total tumor number were significantly reduced. In addition, epidermis of parp-1 À/À mice did not show increased proliferation rates after treatment with carcinogen. Deregulated NF-jB is a hallmark for tumorigenesis together with the concomitant release of early inflammatory mediators. In the absence of PARP-1, NF-jB activation and induction jB-target genes did not take place during the promotion of tumor development. These results suggest that PARP-1 abolition impairs the promotion of skin carcinogenesis interfering with the activation of NF-jB and might have an important implication in targeting PARP-1 as a new antineoplastic therapeutic approach.
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