STAT5b is required for GH-induced liver IGF-I gene expression.

Although the increased expression of Igf-I in liver in response to GH is well characterized, the intracellular signaling pathways that mediate this effect have not been identified. Intracellular signaling molecules belonging to the Janus kinase-signal transducer and activator of transcription 5b (JAK2-STAT5b) pathway are activated by GH and have previously been shown to be required for sexually dimorphic body growth and the expression of liver cytochrome P450 proteins known to be regulated by the gender-specific temporal patterns of pituitary GH secretion. Here, we evaluate the role of STAT5b in GH activation of Igf-I by monitoring the induction of Igf-I mRNA in livers of wild-type and Stat5b(-/-)mice stimulated with exogenous pulses of GH. GH induced the expression of liver Igf-I mRNA in hypophysectomized male wild-type, but not in hypophysectomized male Stat5b(-/-) mice, although the Stat5b(-/-) mice exhibit both normal liver GH receptor expression and strong GH induction of Cytokine-inducible SH2 protein (Cis), which is believed to contribute to the down-regulation of GH-induced liver STAT5b signaling. Thus, STAT5b plays an important and specific role in liver Igf-I gene expression.

Feedback regulation of PRL secretion is mediated by the transcription factor, signal transducer, and activator of transcription 5b.

PRL secretion from the anterior pituitary gland is inhibited by dopamine produced in the tuberoinfundibular dopamine neurons of the hypothalamus. The activity of tuberoinfundibular dopamine neurons is stimulated by PRL; thus, PRL regulates its own secretion by a negative feedback mechanism. PRL receptors are expressed on tuberoinfundibular dopamine neurons, but the intracellular signaling pathway is not known. We have observed that mice with a disrupted signal transducer and activator of transcription 5b gene have grossly elevated serum PRL concentrations. Despite this hyperprolactinemia, mRNA levels and immunoreactivity of tyrosine hydroxylase, the key enzyme in dopamine synthesis, were significantly lower in the tuberoinfundibular dopamine neurons of these signal transducer and activator of transcription 5b-deficient mice. Concentrations of the dopamine metabolite dihydroxyphenylacetic acid in the median eminence were also significantly lower in signal transducer and activator of transcription 5b-deficient mice than in wild-type mice. No changes were observed in nonhypothalamic dopaminergic neuronal populations, indicating that the effects were selective to tuberoinfundibular dopamine neurons. These data indicate that in the absence of signal transducer and activator of transcription 5b, PRL signal transduction in tuberoinfundibular dopamine neurons is impaired, and they demonstrate that this transcription factor plays an obligatory and nonredundant role in mediating the negative feedback action of PRL on tuberoinfundibular dopamine neurons.

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.

STAT5b mediates the GH-induced expression of SOCS-2 and SOCS-3 mRNA in the liver.

Suppressor of cytokine signalling (SOCS) proteins act as part of a classical negative feedback loop regulating cytokine signal transduction. Expression of SOCS proteins is induced in response to cytokines and down-regulates the cytokine signal by inhibiting the JAK/STAT pathway. Growth hormone (GH) was previously shown to induce strong transient expression of SOCS-3 and to a lesser extent CIS, SOCS-1 and SOCS-2 in mouse liver (Adams, T.E., Hansen, J.A., Starr, R., Nicola, N.A., Hilton, D.J., Billestrup, N., 1998. Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signalling. J. Biol. Chem. 273, 1285-1287.). In this work we have compared GH-induced SOCS gene expression in wild-type and STAT5b-deficient mice, and show that STAT5b is required for the induction of SOCS-2 and SOCS-3 in liver. In contrast, the absence of STAT5b has no effect on the GH-induced expression of CIS and SOCS-2 mRNA in the mammary gland. Suprisingly, there is no activation of SOCS-3 expression in mammary glands of wild-type and STAT5b mutant mice following GH administration. These results highlight both tissue- and factor-specific differences in the regulation of SOCS gene expression by STAT5a/b.