GRIM-19 and p16(INK4a) 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 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.
Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Peng
P
Sun
Shreeram C
SC
Nallar
Abhijit
A
Raha
Sudhakar
S
Kalakonda
Chidambaram N
CN
Velalar
Sekhar P
SP
Reddy
Dhananjaya V
DV
Kalvakolanu
D000595:Amino Acid Sequence; D000818:Animals; D017089:Ankyrin Repeat; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary
D051017:Apoptosis Regulatory Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050687:E2F1 Transcription Factor; D019938:Cyclin D1; D009247:NADH, NADPH Oxidoreductases; C439057:NDUFA13 protein, human; D051358:Cyclin-Dependent Kinase 4