No abstract

The tumor suppressor p53 was discovered in 1979 as a cellular protein complexed to the simian virus 40 (SV40) large tumor antigen (LT) (49, 52). Based on the seeming analogy to the complex of the polyoma virus middle T-antigen with the cellular Src protein (12, 13), p53 initially was considered a cellular oncoprotein recruited by LT. This assumption was further supported by experiments demonstrating that p53 was able to immortalize certain primary cells and to cooperate with activated Ras in cellular transformation (27,65,72). However, these initial experiments had been performed with mutant p53 genes, and in 1989 the true nature of p53 as a tumor suppressor was established (31, 42). The discovery of p53 as a tumor suppressor not only spurred research on the role of p53 in tumorigenesis but also led to a renaissance of DNA tumor virus research, as the transforming proteins of polyoma-, papilloma-, and adenoviruses all target the tumor suppressor proteins p53 and pRb (16,22,39,50,53,64,92). Consistent with the functional inactivation of p53 in human and animal tumors, a wealth of evidence demonstrated that the interaction of transforming proteins with p53 also inactivated p53 function.Cellular transformation by SV40 differs from cellular transformation by most other DNA tumor viruses insofar as SV40 LT, the major transforming protein of SV40, is able to perform both major steps of cellular transformation in vitro, immortalization and phenotypic transformation, by itself, while other DNA tumor viruses require the cooperation of at least two viral transforming proteins (11,23,44,48). For example, immortalization of primary cells by the E1A protein of adenovirus or the E7 protein of human papilloma viruses (18,69) requires the functional elimination of the proapoptotic, senescence-inducing functions of p53 by other viral proteins that inactivate p53 (e.g., its sequestration, degradation by the E1B 55K and E4orf6 proteins of adenovirus, or its degradation by the E6 protein of human papillomaviruses) (36,68,77,85,97). Thus, while it is undisputed that SV40 LT eliminates p53 tumor suppressor functions during cellular immortalization, the role of the LT-p53 complex in phenotypic transformation seems to be more complex (33,61). In this respect, our laboratory already in 1987 provided evidence that metabolic stabilization of p53 is not simply a consequence of its physical interaction with LT (19,20) but is an active cellular process that correlates with cellular transformation (21, 87-89, 94, 96). The finding raised the question of why the p53 protein, when destined to be functionally eliminated, should be stabilized during cellular transformation. Also, animal experiments revealed that SV40 is more efficient in promoting tumor growth when wt p53 is present (41). The suggestion that p53 in complex with SV40 LT might support SV40 phenotypic transformation has been received with due skepticism. However, recently it has been reported that human papillomavirus type 16 E6 protein mediated degradation of p53 in SV40-transformed...