Abstract
We have recently isolated novel IFN-inducible gene, Gene associated with Retinoid-Interferon-induced Mortality-1 (GRIM-1), using a genetic technique. Moderate ectopic expression of GRIM-1 caused growth inhibition and sensitized cells to retinoic acid (RA)/IFN-induced cell death while high expression caused apoptosis. GRIM-1 depletion, using RNAi, conferred a growth advantage. Three protein isoforms (1α, 1β and 1γ) with identical C-termini are produced from GRIM-1 mRNA. We show that GRIM-1 isoforms interact with NAF1 and DKC1, two essential proteins required for box H/ACA sno/sca RNP biogenesis and suppresses box H/ACA RNA levels in mammalian cells by delocalizing NAF1. Suppression of these small RNAs manifests as inefficient rRNA maturation and growth suppression. Interestingly, yeast Shq1p also caused growth suppression in mammalian cells. Consistent with its growth-suppressive property, GRIM-1 expression is lost in a number of human primary prostate tumors. Our observations support a recent study that GRIM-1 might act as a co-tumor suppressor in the prostate.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis Regulatory Proteins / genetics*
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Apoptosis Regulatory Proteins / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Growth Processes / drug effects
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Cell Growth Processes / genetics
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Cell Line, Tumor
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Gene Expression Regulation, Neoplastic*
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HeLa Cells
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Humans
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Immunohistochemistry
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Interferon-beta / pharmacology
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Male
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein Binding
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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RNA, Ribosomal / genetics*
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RNA, Ribosomal / metabolism
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RNA, Small Nucleolar / genetics*
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RNA, Small Nucleolar / metabolism
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RNA, Small Untranslated / genetics
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RNA, Small Untranslated / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Ribonucleoproteins / genetics
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Ribonucleoproteins / metabolism
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism
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Tretinoin / pharmacology
Substances
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Apoptosis Regulatory Proteins
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Cell Cycle Proteins
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DKC1 protein, human
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NAF1 protein, human
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Nuclear Proteins
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Protein Isoforms
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RNA, Ribosomal
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RNA, Small Nucleolar
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RNA, Small Untranslated
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Ribonucleoproteins
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Saccharomyces cerevisiae Proteins
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Shq1 protein, S cerevisiae
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Tretinoin
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Interferon-beta