A mutant allele of BARA/LIN-9 rescues the cdk4-/- phenotype by releasing the repression on E2F-regulated genes.
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.
Sandoval
Raudel
R
Department of Pharmacology, University of Illinois at Chicago, IL 60612, USA.
Xue
Jiaping
J
Tian
Xinyong
X
Barrett
Kelly
K
Pilkinton
Mark
M
Ucker
David S
DS
Raychaudhuri
Pradip
P
Kineman
Rhonda D
RD
Luque
Raul M
RM
Baida
Gleb
G
Zou
Xianghong
X
Valli
V E
VE
Cook
James L
JL
Kiyokawa
Hiroaki
H
Colamonici
Oscar R
OR
D000483:Alleles; D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D002453:Cell Cycle; D051358:Cyclin-Dependent Kinase 4 / Q000172:deficiency* / Q000235:genetics; D004247:DNA / Q000096:biosynthesis; D050684:E2F Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000196:embryology; D005260:Female; D005298:Fertility / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism; D010053:Ovary / Q000166:cytology; D010641:Phenotype; D010902:Pituitary Gland / Q000166:cytology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013737:Testis / Q000166:cytology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D050684:E2F Transcription Factors; C414732:LIN-9 protein, C elegans; C501563:LIN9 protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D004247:DNA; D051358:Cyclin-Dependent Kinase 4