UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells.

Abstract

Elevated levels of the p53 cellular tumor antigen have been previously observed in proliferating and transformed mammalian cells. We found that nontransformed mouse cells treated with either UV light or a UV-mimetic chemical carcinogen exhibited a rapid increase in the amount of p53. This stimulation can be explained, at least in part, on the basis of a post-translational stabilization of p53 which is independent of replicative DNA synthesis, consistent with p53 not being an adventitious product of proliferating cells. The results presented here are interpreted in light of the general hypothesis that p53 is involved in the preparation of mammalian cells for DNA synthesis.The p53 cellular tumor antigen is a cellular protein originally observed (14, 17) in murine cells transformed by the DNA tumor virus simian virus 40 (SV40). Subsequently, it has been demonstrated that the levels of this protein are substantially elevated in a variety of systems (for a review, see reference 11), including cells of different mammalian species which have been neoplastically transformed by DNA tumor viruses, isolated from naturally occurring tumors, or stimulated by either mitogens or serum factors to synthesize DNA. The correlation between expression of high levels of p53 and some transformation events or other treatments stimulating cellular growth is reasonably firm and consistent with the hypothesis that p53 functions in the regulation of the transition of mammalian cells to active proliferation. However, the molecular mechanism by which p53 may affect such a transition is at present unknown.The regulation of expression, as well as the possible function, of p53 in neoplastically transformed cells has been most extensively examined in mouse cells transformed by SV40. It has been established that the elevated levels of p53 observed in SV40-transformed mouse cells are a function of the tight interaction (14,17,21,24) of this protein with the SV40-encoded large tumor antigen (T-Ag); this interaction manifests itself in a dramatic increase in the half-lives of both proteins (24). Because of these facts and other demonstrations that the levels of p53 are increased in DNA tumor virus-transformed and proliferating cells, it has been suggested that pS3 functions in the regulation of cellular growth by interacting with viral transforming gene products (22) in virus-transformed cells and, in normal cells, by interacting with a cellular protein(s) (7,15).In general, it is speculated that the precise molecular function of p53 in affecting the transition of cells to active DNA synthesis has to do with the initiation of DNA replication. This suggestion is supported by several lines of evidence: (i) the viral proteins with which p53 interacts in DNA tumor virus-transformed cells are also required for viral DNA replication (8,10,25,29,30), (ii) the stimuli which increase the levels of p53 in nontransformed cells also induce DNA synthesis (7,22), and (iii) cellular transformation or neoplasia can generally be viewed as involving an abrogation of ...

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