TY - JOUR
T1 - The activated aryl hydrocarbon receptor synergizes mitogen-induced murine liver hyperplasia
AU - Mitchell, Kristen A.
AU - Wilson, Shelly R.
AU - Elferink, Cornelis J.
N1 - Funding Information:
Supported by the National Institutes of Environmental Health Sciences (NIEHS) Grants R01ES07800 and P30ES06676 (C.J.E.), F32ES013588 (K.A.M.), F30ES016490 (S.R.W.) and by NIEHS grant T32ES07254 . The authors wish to thank Sean Hattenbach, Carolyn Klocke and Cheri Lamb for technical assistance.
PY - 2010/10
Y1 - 2010/10
N2 - Mechanisms of hepatocyte proliferation triggered by tissue loss are distinguishable from those that promote proliferation in the intact liver in response to mitogens. Previous studies demonstrate that exogenous activation of the aryl hydrocarbon receptor (AhR), a soluble ligand-activated transcription factor in the basic helix-loop-helix family of proteins, suppresses compensatory liver regeneration elicited by surgical partial hepatectomy. The goal of the present study was to determine how AhR activation modulates hepatocyte cell cycle progression in the intact liver following treatment with the hepatomitogen, 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP). Mice were pretreated with the exogenous AhR agonist 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) 24 h prior to treatment with TCPOBOP (3 mg/kg). In contrast to the suppressive effects of AhR activation observed during compensatory regeneration, TCDD pretreatment resulted in a 30-50% increase in hepatocyte proliferation in the intact liver of TCPOBOP-treated mice. Although pretreatment with TCDD suppressed CDK2 kinase activity and increased the association of CDK2 with negative regulatory proteins p21Cip1 and p27Kip1, a corresponding increase in CDK4/cyclin D1 association and CDK4 activity which culminated in enhanced phosphorylation of retinoblastoma protein, consistent with the increased proliferative response. These findings are in stark contrast to previous observations that the activated AhR can suppress hepatocyte proliferation in vivo and reveal a new complexity to AhR-mediated cell cycle control.
AB - Mechanisms of hepatocyte proliferation triggered by tissue loss are distinguishable from those that promote proliferation in the intact liver in response to mitogens. Previous studies demonstrate that exogenous activation of the aryl hydrocarbon receptor (AhR), a soluble ligand-activated transcription factor in the basic helix-loop-helix family of proteins, suppresses compensatory liver regeneration elicited by surgical partial hepatectomy. The goal of the present study was to determine how AhR activation modulates hepatocyte cell cycle progression in the intact liver following treatment with the hepatomitogen, 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP). Mice were pretreated with the exogenous AhR agonist 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) 24 h prior to treatment with TCPOBOP (3 mg/kg). In contrast to the suppressive effects of AhR activation observed during compensatory regeneration, TCDD pretreatment resulted in a 30-50% increase in hepatocyte proliferation in the intact liver of TCPOBOP-treated mice. Although pretreatment with TCDD suppressed CDK2 kinase activity and increased the association of CDK2 with negative regulatory proteins p21Cip1 and p27Kip1, a corresponding increase in CDK4/cyclin D1 association and CDK4 activity which culminated in enhanced phosphorylation of retinoblastoma protein, consistent with the increased proliferative response. These findings are in stark contrast to previous observations that the activated AhR can suppress hepatocyte proliferation in vivo and reveal a new complexity to AhR-mediated cell cycle control.
KW - AhR
KW - Hyperplasia
KW - Liver
KW - TCDD
KW - TCPOBOP
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U2 - 10.1016/j.tox.2010.07.004
DO - 10.1016/j.tox.2010.07.004
M3 - Article
C2 - 20637255
AN - SCOPUS:77956405629
SN - 0300-483X
VL - 276
SP - 103
EP - 109
JO - Toxicology
JF - Toxicology
IS - 2
ER -