Stimulation of hepatic signal transducer and activator of transcription 5b by GH is not altered by 3-methylcholanthrene.
We are investigating the mechanisms by which aromatic hydrocarbons, such as 3-methylcholanthrene (MC), suppress hepatic cytochrome P450 2C11 (CYP2C11) gene expression. CYP2C11 is an enzyme expressed in the liver of male rats and is regulated by a pulsatile pattern of GH secretion. We have previously shown that MC attenuates the stimulatory effect of GH on CYP2C11 expression in hypophysectomized male rats. In follow-up studies we evaluated the effect of MC on GH-stimulated signal transducer and activator of transcription 5b (STAT5b) phosphorylation, nuclear translocation, and DNA-binding activity. GH-stimulated increases in hepatic nuclear STAT5b and phospho-STAT5b levels were not different between groups of hypophysectomized rats receiving MC or vehicle. This observation was corroborated at the DNA-binding level by EMSA. We also measured GH-induced STAT5b activation in the H4IIE rat hepatoma cell line. STAT5b DNA-binding activity detected in GH-treated cells was not affected by MC. Immunocytochemistry experiments revealed no effect of MC on GH-stimulated STAT5b nuclear translocation in H4IIE cells. These in vivo and in vitro data suggest that interference with GH-stimulated STAT5b activation does not constitute a mechanism by which MC attenuates the stimulatory effect of GH on CYP2C11 gene expression.
Department of Pharmacology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Yoav E
YE
Timsit
David S
DS
Riddick
D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D002364:Caseins / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013006:Growth Hormone / Q000494:pharmacology*; D007016:Hypophysectomy; D015151:Immunoblotting; D007150:Immunohistochemistry; D007163:Immunosorbent Techniques; D008099:Liver / Q000737:chemistry*; D008114:Liver Neoplasms, Experimental; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D008894:Milk Proteins; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D002364:Caseins; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; C494097:Stat5b protein, rat; D015534:Trans-Activators; D019000:Phosphotyrosine; D008748:Methylcholanthrene; D013006:Growth Hormone; D004247:DNA