STAT5b-deficient Mice Are Growth Hormone Pulse-resistant

Abstract

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. Growth hormone (GH)1 has diverse effects on metabolism and growth that can result from the direct effects of GH on gene expression, or may be indirectly mediated by factors such as insulin-like growth factor I (1). In addition, the temporal patterns of pituitary GH secretion differ in males and females in many species, resulting in the expression of some genes predominantly in males and other genes predominantly in females (2-4). In male rats, plasma GH pulses are separated by periods of Ͼ2 h during which there is negligible GH detectable in blood. In contrast, the female plasma GH pattern is characterized by a more continuous presence of GH or, in some species such as mice, by more frequent pulses of GH (3,5).GH binds to cell surface receptors that dimerize upon hormone binding and subsequently activate the receptor-associated tyrosine kinase JAK2. JAK2 in turn phosphorylates itself and the GH receptor on multiple tyrosine residues. STAT proteins are then recruited to the GH receptor/JAK2 complex and are phosphorylated on tyrosine and subsequently on serine. STAT proteins activated in this manner form homo-or heterodimers and translocate to the nucleus where they bind to target sites in GH-responsive genes (6, 7). STAT5 proteins in the liver are intermittently, and repeatedly, activated in response to GH pulses (8, 9). GH also activates liver STAT1 and STAT3, but the activation of these STATs is largely ind...

The role of STAT proteins in growth hormone signaling

“…Studies comparing liver gene expression in hypophysectomized normal and STAT5B-de®cient mice given GH pulse replacement support this idea (Davey et al, 1999b).…”

“…Yet other GH signaling molecules are likely to play similarly important roles. Hypophysectomized STAT5B-de®cient male mice given GH pulse replacement suggest that STAT5B is required for pulsatile GH-driven growth (Davey et al, 1999b). However, male and female mice de®cient in STAT5A and STAT5B either alone or in combination still grow, although signi®cantly slower than normal.…”

SOCS/CIS Protein Inhibition of Growth Hormone-stimulated STAT5 Signaling by Multiple Mechanisms

“…GH signaling and transcriptional responses are distinct from those of many other hormones and cytokines by virtue of the sex-dependent temporal patterns of pituitary GH secretion, which confer the observed sexually dimorphic physiological responses to GH, such as pubertal growth rates (51) and liver P450 gene expression (52)(53)(54). STAT5b is a key mediator of the in vivo responses of rodents to the pulsatile plasma GH profile that is characteristic of males (6,9,10,55). Further elucidation of the role of SOCS/CIS proteins in GH signaling will provide for a fuller understanding of the multiple physiological responses to GH, including the repeated activation and deactivation of signaling to liver STAT5b that is stimulated by sequential male plasma GH pulses (6) and the low level STAT5b signaling that becomes established in response to the female plasma GH pattern (7,11).…”

Role of the Cytokine-inducible SH2 Protein CIS in Desensitization of STAT5b Signaling by Continuous Growth Hormone

“…This dependence is most striking in rodent liver, where the intermittent occurrence of strong, well defined plasma GH pulses that is characteristic of adult males stimulates transcription of a set of cytochrome P450 and other genes that is distinct from the set of genes that is transcriptionally activated by the more continuous plasma GH profile associated with adult females (3,10). The sexual dimorphism of GH-regulated liver gene expression is critically dependent on STAT5b, as revealed by mouse knockout studies (11)(12)(13)(14), supporting the proposal that liver STAT5 (primarily STAT5b) is a key mediator of the effects of plasma GH pulses on the male pattern of liver gene expression (15). Liver STAT5b is strongly, and repeatedly, activated in adult male rats in response to each incoming plasma GH pulse (16), while in adult female rats the near continuous presence of GH in plasma leads to substantial down-regulation of GHR-JAK2-dependent signaling to STAT5b (17).…”