The basic carboxy terminus of p53 plays an important role in directing the protein into the nuclear compartment. The C terminus of the p53 molecule contains a cluster of several nuclear localization signals (NLSs) that mediate the migration of the protein into the cell nucleus. NLSI, the most active domain, is highly conserved in genetically diverged species and shares perfect homology with consensus NLS sequences found in other nuclear proteins. The other two NLSs, II and III, appear to be less effective and less conserved. Although nuclear localization is dictated primarily by the NLSs inherent in the primary amino acid sequence, the actual nuclear homing can be modified by interactions with other proteins expressed in the cell. Comparison between wild-type p53 and naturally occurring mutant p53 showed that both protein categories could migrate into the nucleus of rat primary embryonic fibroblasts by essentially similar mechanisms. Nuclear localization of both proteins was totally dependent on the existence of functional NLS domains. In COS cells, however, we found that NLS-deprived wild-type p53 molecules could migrate into the nucleus by complexing with another nuclear protein, simian virus 40 large-T antigen. Wild-type and mutant p53 proteins differentially complexed with viral or cellular proteins, which may significantly affect the ultimate compartmentalization of p53 in the cell; this finding suggests that the actual subcellular compartmentalization of proteins may difer in various cell type milieux and may largely be affected by the ability of these proteins to complex with other proteins expressed in the cell. Experiments designed to test the physiological significance of p53 subcellular localization indicated that nuclear localization of mutant p53 is essential for this protein to enhance the process of malignant transformation of partially transformed cells, suggesting that p53 functions within the cell nucleus.The gene encoding p53 nuclear protein, which has been shown to act as a dominant oncogene (12,14,23,40,45,56,57), was recently reported to function as an antioncogene (13,15,29). Using several experimental approaches, it had initially been found that p53 overproduction enhanced the malignant process. However, recent findings suggest that the mutant p53 gene may enhance the malignant process, whereas the wild-type p53 gene functions as an antioncogene.The hypothesis that the wild-type p53 gene functions as a tumor suppressor gene was initially deduced from the observation that the wild-type protein failed to enhance malignant transformation but rather suppressed the transforming activity of other oncogenes. A comparison of the ability of the various p53 proteins to transform primary embryonic cells in cooperation with the ras oncogene indicated that mutant p53 induced the appearance of morphologically transformed foci, whereas the wild type did not (12,16,22). Finlay et al.(15) showed that wild-type p53 directly suppressed transformation by Ela and ras oncogenes. Eliyahu et al. (13) described a...
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