GRIM-19 and p16INK4a Synergistically Regulate Cell Cycle Progression and E2F1-responsive Gene Expression

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 inactiva...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-09, Vol.285 (36), p.27545-27552
Main Authors: Sun, Peng, Nallar, Shreeram C., Raha, Abhijit, Kalakonda, Sudhakar, Velalar, Chidambaram N., Reddy, Sekhar P., Kalvakolanu, Dhananjaya V.
Format: Article
Language:English
Subjects:
Cancer
Cell Cycle
Cytokine Action
E2F Transcription Factor
Gene Regulation
Growth Suppression
Inhibitors
Interferon
Molecular Bases of Disease
Protein Interaction
Tumor Suppressor
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.105767