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Mutation of BARA/LIN‐9 rescues the CDK4‐null phenotype by releasing the repression on E2F‐regulated genes
Author(s) -
Sandoval Raudel,
Xue Jiaping,
Pilkinton Mark,
Kineman Rhonda,
Luque Raul,
Zou Xianghong,
Kiyokawa Hiroaki,
Colamonici Oscar
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a38-c
Subject(s) - psychological repression , genetics , phenotype , gene
Genetic studies have previously established that C. elegans LIN‐9 functions downstream of cdk‐4 and cyd‐1, homologues of mammalian CDK4/6 and cyclin D respectively, in a distinct pathway that regulates cell proliferation. In this study, we demonstrate that mammalian BARA/LIN‐9 is a nuclear protein that inhibits cell proliferation in a variety of cell lines. More importantly, we determine that BARA/LIN‐9 also acts downstream of CDK4/6 and cyclin D in mammalian cells since i) its anti‐proliferative effect is partially blocked by co‐expression of cyclin D1, and ii) a mutant form that lacks the first 84 amino acids (Δ84) rescues observed phenotypic alterations in fertility and growth in mice null for cdk4 . An analysis of cell cycle proteins indicates the Δ84 mutation of BARA/LIN‐9 restores the expression of E2F target genes in CDK4‐null mouse embryonic fibroblast (MEF) cells. Interestingly, the Δ84 mutation of BARA/LIN‐9 had no effect in mice null for cdk2. These data supports a model in which BARA/LIN‐9 plays an important role in the repression of transcription of genes required for progression through G1 and entry into S phase downstream of CDK4, but independent of CDK2. Support for this work provided by NIH grant GM54709 (ORC) and DK30667 (RDK).