Abstract
GRIM-19 (Gene associated with Retinoid-IFN-induced Mortality-19) was originally isolated as a growth suppressor in a genome-wide knockdown screen with antisense libraries. Like classical tumor suppressors, mutations, and/or loss of GRIM-19 expression occur in primary human tumors; and it is inactivated by viral gene products. Our search for potential GRIM-19-binding proteins, using mass spectrometry, that permit its antitumor actions led to the inhibitor of cyclin-dependent kinase 4, CDKN2A. The GRIM-19/CDKN2A synergistically suppressed cell cycle progression via inhibiting E2F1-driven gene expression. The N terminus of GRIM-19 and the fourth ankyrin repeat of CDKN2A are crucial for their interaction. The biological relevance of these interactions is underscored by observations that GRIM-19 promotes the inhibitory effect of CDKN2A on CDK4; and mutations from primary tumors disrupt its ability to interact with GRIM-19 and suppress E2F1-driven gene expression.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Sequence
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Animals
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Ankyrin Repeat
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Apoptosis Regulatory Proteins / chemistry
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Apoptosis Regulatory Proteins / deficiency
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Cell Cycle*
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Cell Line, Tumor
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Cyclin D1 / metabolism
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Cyclin-Dependent Kinase 4 / metabolism
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Cyclin-Dependent Kinase Inhibitor p16 / chemistry
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
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E2F1 Transcription Factor / metabolism*
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G1 Phase
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Gene Expression Regulation, Neoplastic*
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Gene Knockdown Techniques
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Humans
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Mice
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Molecular Sequence Data
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Mutation
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NADH, NADPH Oxidoreductases / chemistry
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NADH, NADPH Oxidoreductases / deficiency
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NADH, NADPH Oxidoreductases / genetics
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NADH, NADPH Oxidoreductases / metabolism*
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology
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Protein Structure, Tertiary
Substances
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Apoptosis Regulatory Proteins
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Cyclin-Dependent Kinase Inhibitor p16
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E2F1 Transcription Factor
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Cyclin D1
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NADH, NADPH Oxidoreductases
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NDUFA13 protein, human
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Cyclin-Dependent Kinase 4