Abstract
Tumor suppressors of the retinoblastoma susceptibility gene family regulate cell growth and differentiation. Polyomavirus large T antigens (large T) bind Rb family members and block their function. Mutations of large T sequences conserved with the DnaJ family affect large T binding to a cellular DnaK, heat shock protein 70. The same mutations abolish large T activation of E2F-containing promoters and Rb binding-dependent large T activation of cell cycle progression. Cotransfection of a cellular DnaJ domain blocks wild-type large T action, showing that the connection between the chaperone system and tumor suppressors is direct. Although they are inactive in assays dependent on Rb family binding, mutants in the J region retain the ability to associate with pRb, p107, and p130. This suggests that binding of Rb family members by large T is not sufficient for their inactivation and that a functional J domain is required as well. This work connects the DnaJ and DnaK molecular chaperones to regulation of tumor suppressors by polyomavirus large T.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Amino Acid Sequence
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Animals
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Antigens, Polyomavirus Transforming / chemistry
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Antigens, Polyomavirus Transforming / genetics
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Antigens, Polyomavirus Transforming / metabolism*
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Binding Sites
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Carrier Proteins*
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Cell Cycle Proteins*
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DNA-Binding Proteins*
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E2F Transcription Factors
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HSP40 Heat-Shock Proteins
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Heat-Shock Proteins / chemistry
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Heat-Shock Proteins / metabolism*
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Humans
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Mice
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Molecular Sequence Data
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Mutagenesis
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Proteins*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism*
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Retinoblastoma-Binding Protein 1
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Retinoblastoma-Like Protein p107
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Retinoblastoma-Like Protein p130
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Sequence Homology, Amino Acid
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Transcription Factor DP1
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Transcription Factors / genetics
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Transcriptional Activation
Substances
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Antigens, Polyomavirus Transforming
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Arid4a protein, mouse
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Carrier Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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E2F Transcription Factors
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HSP40 Heat-Shock Proteins
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Heat-Shock Proteins
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Nuclear Proteins
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Phosphoproteins
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Proteins
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RBL1 protein, human
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RBL2 protein, human
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Rbl1 protein, mouse
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Rbl2 protein, mouse
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Repressor Proteins
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Retinoblastoma Protein
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Retinoblastoma-Binding Protein 1
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Retinoblastoma-Like Protein p107
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Retinoblastoma-Like Protein p130
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Transcription Factor DP1
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Transcription Factors