STAT5b-deficient mice are growth hormone pulse-resistant. Role of STAT5b in sex-specific liver p450 expression.
The signal transducer and transcriptional activator STAT5b is required to maintain the adult male pattern of liver gene expression and whole body pubertal growth rates, as demonstrated by the loss of these growth hormone (GH) pulse-dependent responses in mice with a targeted disruption of the STAT5b gene. The present study investigates whether these phenotypes of STAT5b-deficient mice result from impaired intracellular GH signaling associated with a loss of GH pulse responsiveness, as contrasted with a feminization of the pituitary GH secretory profile leading to the observed feminization of body growth and liver gene expression. Pulsatile GH replacement in hypophysectomized mice stimulated body weight gain in wild-type but not in STAT5b-deficient mice. Expression of the male-specific liver P450 enzyme CYP2D9, which is reduced to female levels in hypophysectomized male mice, was restored to male levels by GH pulse replacement in wild-type but not in STAT5b-deficient mice. Similarly, a female-specific liver CYP2B P450 enzyme that was up-regulated to female levels following hypophysectomy of males was suppressed to normal basal male levels by GH pulses only in wild-type hypophysectomized mice. Finally, urinary excretion of the male-specific, GH pulse-induced major urinary protein was restored to normal male levels following pulsatile GH treatment only in the case of wild-type hypophysectomized mice. STAT5b-deficient mice are thus GH pulse-resistant, supporting the proposed role of STAT5b as a key intracellular mediator of the stimulatory effects of plasma GH pulses on the male pattern of liver gene expression.
Davey
H W
HW
AgResearch, Ruakura Research Centre, Private Bag 3123, Hamilton, New Zealand. daveyh@agresearch.cri.nz
Park
S H
SH
Grattan
D R
DR
McLachlan
M J
MJ
Waxman
D J
DJ
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003433:Crosses, Genetic; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007016:Hypophysectomy; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008894:Milk Proteins; D010641:Phenotype; D011506:Proteins / Q000032:analysis; D050799:STAT5 Transcription Factor; D012727:Sex Characteristics; D013004:Somatostatin / Q000502:physiology*; D013250:Steroid Hydroxylases / Q000235:genetics*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015430:Weight Gain
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011506:Proteins; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse; D015534:Trans-Activators; C035737:major urinary proteins; D013004:Somatostatin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C022724:testosterone 7-alpha-hydroxylase, hamster