Direct control of cell cycle gene expression by proto-oncogene product ACTR, and its autoregulation underlies its transforming activity

Maggie C. Louie, Alexey S. Revenko, June X Zou, Jennifer Yao, Hongwu Chen

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

ACTR (also called AIB1 and SRC-3) was identified as a coactivator for nuclear receptors and is linked to multiple types of human cancer due to its frequent overexpression. However, the molecular mechanism of ACTR oncogenicity and its function independent of nuclear receptors remain to be defined. We demonstrate here that ACTR is required for both normal and malignant human cells to effectively enter S phase. RNA interference-mediated depletion and chromatin immunoprecipitation assays show that endogenous ACTR directly controls the expression of genes important for initiation of DNA replication, which include cdc6, cdc25A, MCM7, cyclin E, and Cdk2. Moreover, consistent with its critical role in cell cycle control, ACTR expression appears to be cell cycle regulated, which involves E2F. Interestingly, ACTR is recruited to its own promoter at the G1/S transition and activates its own expression, suggesting a positive feedback mechanism for ACTR action in the control of cell cycle progression and for its aberrant expression in cancers. Importantly, overexpression of ACTR alone transforms human mammary epithelial cells, which requires its association with E2F. These findings reveal a novel role for ACTR in cell cycle control and support the notion that the ability of aberrant ACTR to deregulate the cell cycle through E2F underlies its oncogenicity in human cancers.

Original languageEnglish (US)
Pages (from-to)3810-3823
Number of pages14
JournalMolecular and Cellular Biology
Volume26
Issue number10
DOIs
StatePublished - May 2006

Fingerprint

cdc Genes
Proto-Oncogenes
Oncogene Proteins
Homeostasis
Cell Cycle Checkpoints
Gene Expression
Cell Cycle
Nuclear Receptor Coactivators
Cyclin E
Neoplasms
Chromatin Immunoprecipitation
Cytoplasmic and Nuclear Receptors
RNA Interference
DNA Replication
S Phase
Breast
Epithelial Cells

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Direct control of cell cycle gene expression by proto-oncogene product ACTR, and its autoregulation underlies its transforming activity. / Louie, Maggie C.; Revenko, Alexey S.; Zou, June X; Yao, Jennifer; Chen, Hongwu.

In: Molecular and Cellular Biology, Vol. 26, No. 10, 05.2006, p. 3810-3823.

Research output: Contribution to journalArticle

@article{29cef41d2a2e4fe1bacbbc60991311a5,
title = "Direct control of cell cycle gene expression by proto-oncogene product ACTR, and its autoregulation underlies its transforming activity",
abstract = "ACTR (also called AIB1 and SRC-3) was identified as a coactivator for nuclear receptors and is linked to multiple types of human cancer due to its frequent overexpression. However, the molecular mechanism of ACTR oncogenicity and its function independent of nuclear receptors remain to be defined. We demonstrate here that ACTR is required for both normal and malignant human cells to effectively enter S phase. RNA interference-mediated depletion and chromatin immunoprecipitation assays show that endogenous ACTR directly controls the expression of genes important for initiation of DNA replication, which include cdc6, cdc25A, MCM7, cyclin E, and Cdk2. Moreover, consistent with its critical role in cell cycle control, ACTR expression appears to be cell cycle regulated, which involves E2F. Interestingly, ACTR is recruited to its own promoter at the G1/S transition and activates its own expression, suggesting a positive feedback mechanism for ACTR action in the control of cell cycle progression and for its aberrant expression in cancers. Importantly, overexpression of ACTR alone transforms human mammary epithelial cells, which requires its association with E2F. These findings reveal a novel role for ACTR in cell cycle control and support the notion that the ability of aberrant ACTR to deregulate the cell cycle through E2F underlies its oncogenicity in human cancers.",
author = "Louie, {Maggie C.} and Revenko, {Alexey S.} and Zou, {June X} and Jennifer Yao and Hongwu Chen",
year = "2006",
month = "5",
doi = "10.1128/MCB.26.10.3810-3823.2006",
language = "English (US)",
volume = "26",
pages = "3810--3823",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "10",

}

TY - JOUR

T1 - Direct control of cell cycle gene expression by proto-oncogene product ACTR, and its autoregulation underlies its transforming activity

AU - Louie, Maggie C.

AU - Revenko, Alexey S.

AU - Zou, June X

AU - Yao, Jennifer

AU - Chen, Hongwu

PY - 2006/5

Y1 - 2006/5

N2 - ACTR (also called AIB1 and SRC-3) was identified as a coactivator for nuclear receptors and is linked to multiple types of human cancer due to its frequent overexpression. However, the molecular mechanism of ACTR oncogenicity and its function independent of nuclear receptors remain to be defined. We demonstrate here that ACTR is required for both normal and malignant human cells to effectively enter S phase. RNA interference-mediated depletion and chromatin immunoprecipitation assays show that endogenous ACTR directly controls the expression of genes important for initiation of DNA replication, which include cdc6, cdc25A, MCM7, cyclin E, and Cdk2. Moreover, consistent with its critical role in cell cycle control, ACTR expression appears to be cell cycle regulated, which involves E2F. Interestingly, ACTR is recruited to its own promoter at the G1/S transition and activates its own expression, suggesting a positive feedback mechanism for ACTR action in the control of cell cycle progression and for its aberrant expression in cancers. Importantly, overexpression of ACTR alone transforms human mammary epithelial cells, which requires its association with E2F. These findings reveal a novel role for ACTR in cell cycle control and support the notion that the ability of aberrant ACTR to deregulate the cell cycle through E2F underlies its oncogenicity in human cancers.

AB - ACTR (also called AIB1 and SRC-3) was identified as a coactivator for nuclear receptors and is linked to multiple types of human cancer due to its frequent overexpression. However, the molecular mechanism of ACTR oncogenicity and its function independent of nuclear receptors remain to be defined. We demonstrate here that ACTR is required for both normal and malignant human cells to effectively enter S phase. RNA interference-mediated depletion and chromatin immunoprecipitation assays show that endogenous ACTR directly controls the expression of genes important for initiation of DNA replication, which include cdc6, cdc25A, MCM7, cyclin E, and Cdk2. Moreover, consistent with its critical role in cell cycle control, ACTR expression appears to be cell cycle regulated, which involves E2F. Interestingly, ACTR is recruited to its own promoter at the G1/S transition and activates its own expression, suggesting a positive feedback mechanism for ACTR action in the control of cell cycle progression and for its aberrant expression in cancers. Importantly, overexpression of ACTR alone transforms human mammary epithelial cells, which requires its association with E2F. These findings reveal a novel role for ACTR in cell cycle control and support the notion that the ability of aberrant ACTR to deregulate the cell cycle through E2F underlies its oncogenicity in human cancers.

UR - http://www.scopus.com/inward/record.url?scp=33646577780&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646577780&partnerID=8YFLogxK

U2 - 10.1128/MCB.26.10.3810-3823.2006

DO - 10.1128/MCB.26.10.3810-3823.2006

M3 - Article

VL - 26

SP - 3810

EP - 3823

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 10

ER -