Impaired nuclear translocation, cytoplasmic accumulation of nuclear protein and alteration of cellular physiology

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Nuclear transport of transcription factor p53 and cFos, a several nuclear body-forming proteins, and their regulation of biological functions were investigated. Young human fibroblasts transport p53 to the nuclei. However, in senescent adult skin fibroblasts, p53 protein accumulated in the cytoplasm dominantly and localized on vimentin cytoskeleton. Ectopically expressed p53-GFP of senescent cells, retained in the cytoplasm. Nuclear transport system of senescent cells is still functional, because the nuclear import of histon H2B and hnRNP ALF-C1 is not impaired. Therefore, the impaired nuclear transport of p53 seems to be due to the anchoring to vimentin cytoskeleton. This anchoring needs the conformational change of p53,which may be induced by phosphorylation of p53. Thus the senescent cells seem to produce a putative p53-kinase which modifies the conformation of p53.S1-1 protein was discovered by Akira Inoue in 1996. So far the biological function and molecular property have been remained unknown. Through this study, I found that S1-1 protein family, p110 (full length 852AA) and p130 (full length 929AA) formed the distinct nuclear body. Primary alignment analysis of S1-1 and PML (promyelocytic leukemia) isoforms revealed the two highly conserved domains, which were termed EGKE and Z domains. Z domain was identified as a responsible molecular region for S1-1 nuclear body formation. Removal of the Z-domain significantly impaired the nuclear body formation of S1-1 and PML4. Ectopically expressed PML4 accumulated in the cytoplasm of cos7 cells. This cytoplasmic retention needs the distinct domain which exists in the carboxyterminal 74 amino acids.Cytoplasmic retention or accumulation of the distinct nuclear proteins depends on the existence of their distinct domains post-tranlational modification, and altered conformation. It is interesting if vimentin cytoskeleton involves with the cytoplasmic retention of PML4.