title: Inactivation of pRB-related proteins p130 and p107 mediated by the J domain of simian virus 40 large T antigen.
abstract: Inactivation of the retinoblastoma tumor suppressor protein (pRB) contributes to tumorigenesis in a wide variety of cancers. In contrast, the role of the two pRB-related proteins, p130 and p107, in oncogenic transformation is unclear. The LXCXE domain of simian virus 40 large T antigen (TAg) specifically binds to pRB, p107, and p130. We have previously shown that the N terminus and the LXCXE domain of TAg cooperate to alter the phosphorylation state of p130 and p107. Here, we demonstrate that TAg promotes the degradation of p130 and that the N terminus of TAg is required for this activity. The N terminus of TAg has homology to the J domain of the DnaJ family of molecular chaperone proteins. Mutants with mutations in the J-domain homology region of TAg are defective for altering p130 and p107 phosphorylation and for p130 degradation. A heterologous J-domain from a human DnaJ protein can functionally 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 homology region of TAg confers a growth advantage to wild-type mouse embryo fibroblasts (MEFs) but is dispensable in the case of MEFs lacking both p130 and p107. This indicates that p107 and p130 have overlapping growth-suppressing activities whose inactivation is mediated by the J domain of TAg.
authors.affiliation: Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: H
authors.initials: H
authors.lastname: Stubdal
authors.forename: J
authors.initials: J
authors.lastname: Zalvide
authors.forename: K S
authors.initials: KS
authors.lastname: Campbell
authors.forename: C
authors.initials: C
authors.lastname: Schweitzer
authors.forename: T M
authors.initials: TM
authors.lastname: Roberts
authors.forename: J A
authors.initials: JA
authors.lastname: DeCaprio
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors*; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000737:chemistry; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011506:Proteins; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors*; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D016415:Sequence Alignment; D014407:Tumor Cells, Cultured
chemical_list: D000952:Antigens, Polyomavirus Transforming; D006131:Growth Inhibitors; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; C493844:RBL1 protein, human; C493837:RBL2 protein, human; C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex