INACTIVATION OF PRB-RELATED PROTEINS P130 AND P107 MEDIATED BY THE J-DOMAIN OF SIMIAN-VIRUS-40 LARGE T-ANTIGEN

Inactivation of the retinoblastoma tumor suppressor protein (pRB) cont ributes to tumorigenesis in a wide variety of cancers. In contrast, th e role of the two pRB-related proteins, p130 and p107, in oncogenic tr ansformation is unclear. The LXCXE domain of simian virus 40 large T a ntigen (TAg) specifically binds to pRB, p107, and p130. We have previo usly shown that the N terminus and the LXCXE domain of TAg cooperate t o alter the phosphorylation state of p130 and p107. Here, we demonstra te that TAg promotes the degradation of p130 and that the N terminus o f TAg is required for this activity. The N terminus of TAg has homolog y to the J domain of the DnaJ family of molecular chaperone proteins. Mutants with mutations in the J domain homology region of TAg are defe ctive for altering p130 and p107 phosphorylation and for p130 degradat ion. A heterologous J-domain from a human DnaJ protein can functionall y substitute for the N terminus of TAg in the effect on p107 and p130 phosphorylation and p130 stability. We further demonstrate that the J- domain homolog region of TAg confers a growth advantage to wild-type m ouse embryo fibroblasts (MEFs) but is dispensable in the case of MEFs lacking both p130 and p107. This indicates that p107 and p130 have ove rlapping growth-suppressing activities whose inactivation is mediated by the J domain of TAg.