Phospho-STAT5 accumulation in nuclear fractions from vitamin A-deficient rat liver.
The growth hormone (GH)-responsive cytochrome P450 (CYP) 2C11 is down-regulated in vitamin A-deficient (VAD) rat liver. This study assessed the impact of a VAD diet on the hepatic Janus kinase-Signal Transducers and Activators of Transcription (JAK-STAT) system that mediates GH signalling. Nuclear tyrosine- and serine-phosphorylated STAT5 accumulated in VAD liver, whereas nuclear JAK2 tyrosine kinase and SHP-1 phosphatase were decreased. Tyrosine-phosphorylated SHP-1 was decreased to 36+/-14% of control (P<0.01), indicating its impaired activation in VAD liver. Episodic GH pulses increased nuclear phospho-STAT5, especially in control liver, but nuclear phospho-JAK2 and phospho-SHP-1 were not restored. CYP2C11 protein and testosterone 16alpha-hydroxylation were decreased in VAD liver to 67+/-16% and 76+/-19% of control, and were further decreased by GH to 32+/-8% and 30+/-14% of control. Thus, hypo-responsiveness of JAK-STAT in VAD liver is associated with impaired nuclear phospho-STAT dephosphorylation.
Murray
Michael
M
Pharmacogenomics and Drug Development Group, Faculty of Pharmacy, University of Sydney, NSW 2006, Australia. michaelm@pharm.usyd.edu.au
Butler
Alison M
AM
Fiala-Beer
Eva
E
Su
Gloria M
GM
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D013006:Growth Hormone / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D008099:Liver / Q000378:metabolism*; D008297:Male; D008894:Milk Proteins / Q000032:analysis / Q000378:metabolism*; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D050799:STAT5 Transcription Factor; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism; D014802:Vitamin A Deficiency / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014801:Vitamin A; D013739:Testosterone; D014443:Tyrosine; D012694:Serine; 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; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509250:Ptpn6 protein, rat