INACTIVATION OF TUMOR-SUPPRESSOR P53 BY MOT-2, A HSP70 FAMILY MEMBER

The mortalin genes, mot-1 and mot-2, are hsp70 family members that wer e originally cloned from normal and immortal murine cells, respectivel y. Their proteins differ by only two amino acid residues but exhibit d ifferent subcellular localizations, arise from two distinct genes, and have contrasting biological activities. We report here that the two p roteins also differ in their interactions with the tumor suppressor pr otein p53. The pancytosolic mot-1 protein in normal cells did not show colocalization with p53; in contrast, nonpancytosolic mot-2 and p53 o verlapped significantly in immortal cells. Transfection of mot-2 but n ot mot-1 resulted in the repression of p53-mediated transactivation in p53-responsive reporter assays. Inactivation of p53 by mot-2 was supp orted by the down-regulation of p53-responsive genes p21(WAF-1) and md m-2 in mot-2-transfected cells only. Furthermore, NIH 3T3 cells transf ected with expression plasmid encoding green fluorescent protein-tagge d mot-2 but not mot-1 showed an abrogation of nuclear translocation of wild-type p53. These results demonstrate a novel mechanism of p53 ina ctivation by mot-2 protein.