A mutant allele of BARA/LIN-9 rescues the cdk4-/- phenotype by releasing the repression on E2F-regulated genes

Raudel Sandoval; Jiaping Xue; Xinyong Tian; Kelly Barrett; Mark Pilkinton; David S. Ucker; Pradip Raychaudhuri; Rhonda D. Kineman; Raul M. Luque; Gleb Baida; Xianghong Zou; V. E. Valli; James L. Cook; Hiroaki Kiyokawa; Oscar R. Colamonici

doi:10.1016/j.yexcr.2006.04.002

A mutant allele of BARA/LIN-9 rescues the cdk4^-/- phenotype by releasing the repression on E2F-regulated genes

Raudel Sandoval, Jiaping Xue, Xinyong Tian, Kelly Barrett, Mark Pilkinton, David S. Ucker, Pradip Raychaudhuri, Rhonda D. Kineman, Raul M. Luque, Gleb Baida, Xianghong Zou, V. E. Valli, James L. Cook, Hiroaki Kiyokawa, Oscar R. Colamonici^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2465-2475
Number of pages	11
Journal	Experimental Cell Research
Volume	312
Issue number	13
DOIs	https://doi.org/10.1016/j.yexcr.2006.04.002
State	Published - Aug 1 2006

Funding

We are grateful to Dr. Derrick Rancourt for providing us with the targeting vector. We would like to thank Dr. Phillipp Kaldis for the critical review of this manuscript, Drs. T. Yu and Z. Du for producing the pCMV4-myc-BARA-L and GFP-BARA-L constructs, and D. Salvi for technical assistance. This work has been partially supported by NIH grant GM54709 (ORC) and DK30667 (RDK).

Keywords

BARA
CDK
Cell cycle
Cyclin
LIN-9

ASJC Scopus subject areas

Cell Biology

Access to Document

10.1016/j.yexcr.2006.04.002

Cite this

Sandoval, R., Xue, J., Tian, X., Barrett, K., Pilkinton, M., Ucker, D. S., Raychaudhuri, P., Kineman, R. D., Luque, R. M., Baida, G., Zou, X., Valli, V. E., Cook, J. L., Kiyokawa, H., & Colamonici, O. R. (2006). A mutant allele of BARA/LIN-9 rescues the cdk4^-/- phenotype by releasing the repression on E2F-regulated genes. Experimental Cell Research, 312(13), 2465-2475. https://doi.org/10.1016/j.yexcr.2006.04.002

@article{4bedea41fe4d499dad8cdbae5a4ff471,

title = "A mutant allele of BARA/LIN-9 rescues the cdk4-/- phenotype by releasing the repression on E2F-regulated genes",

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.",

keywords = "BARA, CDK, Cell cycle, Cyclin, LIN-9",

author = "Raudel Sandoval and Jiaping Xue and Xinyong Tian and Kelly Barrett and Mark Pilkinton and Ucker, {David S.} and Pradip Raychaudhuri and Kineman, {Rhonda D.} and Luque, {Raul M.} and Gleb Baida and Xianghong Zou and Valli, {V. E.} and Cook, {James L.} and Hiroaki Kiyokawa and Colamonici, {Oscar R.}",

note = "Funding Information: We are grateful to Dr. Derrick Rancourt for providing us with the targeting vector. We would like to thank Dr. Phillipp Kaldis for the critical review of this manuscript, Drs. T. Yu and Z. Du for producing the pCMV4-myc-BARA-L and GFP-BARA-L constructs, and D. Salvi for technical assistance. This work has been partially supported by NIH grant GM54709 (ORC) and DK30667 (RDK).",

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doi = "10.1016/j.yexcr.2006.04.002",

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Sandoval, R, Xue, J, Tian, X, Barrett, K, Pilkinton, M, Ucker, DS, Raychaudhuri, P, Kineman, RD, Luque, RM, Baida, G, Zou, X, Valli, VE, Cook, JL, Kiyokawa, H & Colamonici, OR 2006, 'A mutant allele of BARA/LIN-9 rescues the cdk4^-/- phenotype by releasing the repression on E2F-regulated genes', Experimental Cell Research, vol. 312, no. 13, pp. 2465-2475. https://doi.org/10.1016/j.yexcr.2006.04.002

TY - JOUR

T1 - A mutant allele of BARA/LIN-9 rescues the cdk4-/- phenotype by releasing the repression on E2F-regulated genes

AU - Sandoval, Raudel

AU - Xue, Jiaping

AU - Tian, Xinyong

AU - Barrett, Kelly

AU - Pilkinton, Mark

AU - Ucker, David S.

AU - Raychaudhuri, Pradip

AU - Kineman, Rhonda D.

AU - Luque, Raul M.

AU - Baida, Gleb

AU - Zou, Xianghong

AU - Valli, V. E.

AU - Cook, James L.

AU - Kiyokawa, Hiroaki

AU - Colamonici, Oscar R.

N1 - Funding Information: We are grateful to Dr. Derrick Rancourt for providing us with the targeting vector. We would like to thank Dr. Phillipp Kaldis for the critical review of this manuscript, Drs. T. Yu and Z. Du for producing the pCMV4-myc-BARA-L and GFP-BARA-L constructs, and D. Salvi for technical assistance. This work has been partially supported by NIH grant GM54709 (ORC) and DK30667 (RDK).

PY - 2006/8/1

Y1 - 2006/8/1

N2 - 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.

AB - 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.

KW - BARA

KW - CDK

KW - Cell cycle

KW - Cyclin

KW - LIN-9

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DO - 10.1016/j.yexcr.2006.04.002

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