Multiple mechanisms are involved in Ah receptor-mediated cell cycle arrest

Gengming Huang, Cornelis Elferink

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

The liver is the only solid organ that can respond to major tissue loss or damage by regeneration to restore liver biomass. The aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can disrupt the regenerative process, as evidenced by suppression of DNA synthesis in rat primary hepatocytes in culture and in vivo liver regeneration after partial hepatectomy. Independent observations demonstrated that AhR-mediated G 1 phase cell cycle arrest depends on an interaction with the retinoblastoma tumor suppressor protein (pRb), but differences exist regarding proposed mechanisms of action. Two distinct models have been proposed, one supporting the AhR-pRb interaction functioning in corepression of E2F activity and the other favoring an AhR-pRb interaction participating in transcriptional coactivation of genes encoding G1 phase regulatory proteins. In the present study, experiments in rat hepatoma cells using dominant-negative DNA-binding-defective AhR and Ah receptor nuclear translocator (Arnt) mutants provided evidence that TCDD-induced AhR-mediated G1 arrest is only partially regulated by direct AhR transcriptional activity, suggesting that both coactivation and corepression are involved. Studies using a small interfering RNA to down-regulate Arnt protein expression revealed that TCDD-induced G 1 arrest is absolutely dependent on the Arnt protein.

Original languageEnglish (US)
Pages (from-to)88-96
Number of pages9
JournalMolecular Pharmacology
Volume67
Issue number1
DOIs
StatePublished - Jan 2005

Fingerprint

Aryl Hydrocarbon Receptors
Cell Cycle Checkpoints
Aryl Hydrocarbon Receptor Nuclear Translocator
Tumor Suppressor Proteins
Retinoblastoma Protein
Liver Regeneration
Liver
DNA
G1 Phase
Hepatectomy
Cytoplasmic and Nuclear Receptors
Biomass
Small Interfering RNA
Regeneration
Hepatocytes
Hepatocellular Carcinoma
Down-Regulation
Genes

ASJC Scopus subject areas

  • Pharmacology

Cite this

Multiple mechanisms are involved in Ah receptor-mediated cell cycle arrest. / Huang, Gengming; Elferink, Cornelis.

In: Molecular Pharmacology, Vol. 67, No. 1, 01.2005, p. 88-96.

Research output: Contribution to journalArticle

@article{fad616e2b46742a9951df169c1e2a7e3,
title = "Multiple mechanisms are involved in Ah receptor-mediated cell cycle arrest",
abstract = "The liver is the only solid organ that can respond to major tissue loss or damage by regeneration to restore liver biomass. The aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can disrupt the regenerative process, as evidenced by suppression of DNA synthesis in rat primary hepatocytes in culture and in vivo liver regeneration after partial hepatectomy. Independent observations demonstrated that AhR-mediated G 1 phase cell cycle arrest depends on an interaction with the retinoblastoma tumor suppressor protein (pRb), but differences exist regarding proposed mechanisms of action. Two distinct models have been proposed, one supporting the AhR-pRb interaction functioning in corepression of E2F activity and the other favoring an AhR-pRb interaction participating in transcriptional coactivation of genes encoding G1 phase regulatory proteins. In the present study, experiments in rat hepatoma cells using dominant-negative DNA-binding-defective AhR and Ah receptor nuclear translocator (Arnt) mutants provided evidence that TCDD-induced AhR-mediated G1 arrest is only partially regulated by direct AhR transcriptional activity, suggesting that both coactivation and corepression are involved. Studies using a small interfering RNA to down-regulate Arnt protein expression revealed that TCDD-induced G 1 arrest is absolutely dependent on the Arnt protein.",
author = "Gengming Huang and Cornelis Elferink",
year = "2005",
month = "1",
doi = "10.1124/mol.104.002410",
language = "English (US)",
volume = "67",
pages = "88--96",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Multiple mechanisms are involved in Ah receptor-mediated cell cycle arrest

AU - Huang, Gengming

AU - Elferink, Cornelis

PY - 2005/1

Y1 - 2005/1

N2 - The liver is the only solid organ that can respond to major tissue loss or damage by regeneration to restore liver biomass. The aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can disrupt the regenerative process, as evidenced by suppression of DNA synthesis in rat primary hepatocytes in culture and in vivo liver regeneration after partial hepatectomy. Independent observations demonstrated that AhR-mediated G 1 phase cell cycle arrest depends on an interaction with the retinoblastoma tumor suppressor protein (pRb), but differences exist regarding proposed mechanisms of action. Two distinct models have been proposed, one supporting the AhR-pRb interaction functioning in corepression of E2F activity and the other favoring an AhR-pRb interaction participating in transcriptional coactivation of genes encoding G1 phase regulatory proteins. In the present study, experiments in rat hepatoma cells using dominant-negative DNA-binding-defective AhR and Ah receptor nuclear translocator (Arnt) mutants provided evidence that TCDD-induced AhR-mediated G1 arrest is only partially regulated by direct AhR transcriptional activity, suggesting that both coactivation and corepression are involved. Studies using a small interfering RNA to down-regulate Arnt protein expression revealed that TCDD-induced G 1 arrest is absolutely dependent on the Arnt protein.

AB - The liver is the only solid organ that can respond to major tissue loss or damage by regeneration to restore liver biomass. The aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can disrupt the regenerative process, as evidenced by suppression of DNA synthesis in rat primary hepatocytes in culture and in vivo liver regeneration after partial hepatectomy. Independent observations demonstrated that AhR-mediated G 1 phase cell cycle arrest depends on an interaction with the retinoblastoma tumor suppressor protein (pRb), but differences exist regarding proposed mechanisms of action. Two distinct models have been proposed, one supporting the AhR-pRb interaction functioning in corepression of E2F activity and the other favoring an AhR-pRb interaction participating in transcriptional coactivation of genes encoding G1 phase regulatory proteins. In the present study, experiments in rat hepatoma cells using dominant-negative DNA-binding-defective AhR and Ah receptor nuclear translocator (Arnt) mutants provided evidence that TCDD-induced AhR-mediated G1 arrest is only partially regulated by direct AhR transcriptional activity, suggesting that both coactivation and corepression are involved. Studies using a small interfering RNA to down-regulate Arnt protein expression revealed that TCDD-induced G 1 arrest is absolutely dependent on the Arnt protein.

UR - http://www.scopus.com/inward/record.url?scp=11244353490&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=11244353490&partnerID=8YFLogxK

U2 - 10.1124/mol.104.002410

DO - 10.1124/mol.104.002410

M3 - Article

VL - 67

SP - 88

EP - 96

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 1

ER -