Abstract
It has been proposed that C. elegans LIN-9 functions downstream of CDK4 in a pathway that regulates cell proliferation. Here, we report that mammalian BARA/LIN-9 is a predominantly nuclear protein that inhibits cell proliferation. More importantly, we demonstrate that BARA/LIN-9 also acts downstream of cyclin D/CDK4 in mammalian cells since (i) its antiproliferative effect is partially blocked by coexpression of cyclin D1, and (ii) a mutant form that lacks the first 84 amino acids rescues several phenotypic alterations observed in mice null for cdk4. Interestingly, mutation of BARA/LIN-9 restores the expression of E2F target genes in CDK4 null MEFs, indicating that the wild-type protein plays a role in the expression of genes required for the G1/S transition.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Alleles*
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Animals
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Caenorhabditis elegans Proteins / genetics*
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Caenorhabditis elegans Proteins / metabolism*
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Cell Cycle
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Cyclin-Dependent Kinase 4 / deficiency*
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Cyclin-Dependent Kinase 4 / genetics
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DNA / biosynthesis
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E2F Transcription Factors / antagonists & inhibitors*
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E2F Transcription Factors / metabolism
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Embryo, Mammalian / embryology
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Female
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Fertility / genetics
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Fibroblasts / cytology
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Gene Deletion
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Gene Expression Regulation
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Humans
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Male
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Mice
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Mutation / genetics*
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NIH 3T3 Cells
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Nuclear Proteins / metabolism
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Ovary / cytology
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Phenotype
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Pituitary Gland / cytology
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Repressor Proteins / antagonists & inhibitors*
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Repressor Proteins / metabolism
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Testis / cytology
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Tumor Suppressor Proteins / metabolism
Substances
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Caenorhabditis elegans Proteins
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E2F Transcription Factors
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LIN-9 protein, C elegans
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LIN9 protein, human
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Nuclear Proteins
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Repressor Proteins
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Tumor Suppressor Proteins
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DNA
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Cyclin-Dependent Kinase 4