Inadequacy of the Janus kinase 2/signal transducer and activator of transcription signal transduction pathway to mediate episodic growth hormone-dependent regulation of hepatic CYP2C11.
CYP2C11, the most commonly expressed hepatic cytochrome P450 isoform in male rats, is induced by the masculine "episodic" secretory growth hormone profile. A considerable number of reports have indicated that episodic growth hormone effects are mediated by the activation of the Janus kinase 2 (Jak2)/signal transducer and activator of transcription (Stat)5B signal transduction pathway. We observed that restoration of the normal masculine plasma growth hormone pulse in hypophysectomized male rats did indeed rapidly activate (phosphorylate) Jak2, shortly followed by activation and nuclear translocation of Stat5B. Infusion of a growth hormone pulse with an amplitude that was 10% of the normal height induced a dramatic overexpression of CYP2C11, had little effect activating Jak2, but induced a more rapid and greater accumulation of activated nuclear Stat5B. Restoration of a growth hormone pulse with an amplitude of only 1% of normal had little effect phosphorylating Jak2, activated and translocated to the hepatic nucleus approximately 70% of the normally induced levels of Stat5B, but had no inductive effect on CYP2C11. Last, the hypophysectomized male rat receiving no growth hormone replacement expressed 25 to 35% of normal concentrations of CYP2C11 despite no measurable activation of either Jak2 or Stat5B. These results raise concerns regarding the requisite role of the Jak2/Stat5B pathway in mediating episodic growth hormone regulation of CYP2C11. However, accumulation of activated extracellular signal-regulated kinase (ERK)1 and ERK2 were the only transducers measured in the study not affected by the 1% replacement pulse of growth hormone and were elevated 2- to 3-fold above normal when the pulse was renaturalized to 10% of physiological amplitude, suggesting the possible involvement of mitogen-activated protein kinase in episodic growth hormone regulation of CYP2C11.
Verma
Ashish S
AS
Laboratories of Biochemistry, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce St., Philadelphia, PA 19104-6048, USA.
Dhir
Ravindra N
RN
Shapiro
Bernard H
BH
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015152:Blotting, Northern; D000072467:Cytochrome P450 Family 2; D004268:DNA-Binding Proteins / Q000502:physiology*; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D013006:Growth Hormone / Q000494:pharmacology*; D007016:Hypophysectomy; D053614:Janus Kinase 2; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D008297:Male; D008894:Milk Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D039181:Steroid 16-alpha-Hydroxylase / Q000235:genetics*; D015534:Trans-Activators / Q000502:physiology*
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; C494097:Stat5b protein, rat; D015534:Trans-Activators; D013006:Growth Hormone; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3