Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression

Abstract

The signal transducer and activator of transcription, STAT5b, has been implicated in signal transduction pathways for a number of cytokines and growth factors, including growth hormone (GH). Pulsatile but not continuous GH exposure activates liver STAT5b by tyrosine phosphorylation, leading to dimerization, nuclear translocation, and transcriptional activation of the STAT, which is proposed to play a key role in regulating the sexual dimorphism of liver gene expression induced by pulsatile plasma GH. We have evaluated the importance of STAT5b for the physiological effects of GH pulses using a mouse gene knockout model. STAT5b gene disruption led to a major loss of multiple, sexually differentiated responses associated with the sexually dimorphic pattern of pituitar y GH secretion. Malecharacteristic body growth rates and male-specific liver gene expression were decreased to wild-type female levels in STAT5b ؊͞؊ males, while female-predominant liver gene products were increased to a level intermediate between wild-type male and female levels. Although these responses are similar to those observed in GH-deficient Little mice, STAT5b ؊͞؊ mice are not GH-deficient, suggesting that they may be GH pulseresistant. Indeed, the dwarfism, elevated plasma GH, low plasma insulin-like growth factor I, and development of obesity seen in STAT5b ؊͞؊ mice are all characteristics of Laron-type dwarfism, a human GH-resistance disease generally associated with a defective GH receptor. The requirement of STAT5b to maintain sexual dimorphism of body growth rates and liver gene expression suggests that STAT5b may be the major, if not the sole, STAT protein that mediates the sexually dimorphic effects of GH pulses in liver and perhaps other target tissues. STAT5b thus has unique physiological functions for which, surprisingly, the highly homologous STAT5a is unable to substitute.

IL-2 and long-term T cell activation induce physical and functional interaction between STAT5 and ETS transcription factors in human T cells

“…Presence of Stat5 in the C2p inducible complex is in line with one of its roles evidenced in mice defective for Stat5 expression (Feldman et al, 1997;Imada et al, 1998;Moriggl et al, 1999;Nakajima et al, 1997;Teglund et al, 1998;Udy et al, 1997). The phenotype of peripheral T cells from Stat5a/b-de®cient mice, opposed to single knock-out, revealed a crucial and interchangeable role for these proteins in IL-2 signaling (Moriggl et al, 1999).…”

Prolactin gene-disruption arrests mammary gland development and retards T-antigen-induced tumor growth

“…Tyrosine phosphorylation of Stat5, in particular, has been implicated in mammary growth and development Wakao et al, 1994). Gene disruption of Stat5a results in a phenotype of lactational failure, which may be partially compensated by Stat5b Teglund et al, 1998;Udy et al, 1997). To test the integrity of the PRL signal transduction in the mammary gland we compared Stat activation in PRL 7/7 and PRL +/7 mice by assaying DNA-binding and tyrosine phosphorylation.…”

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

“…Originally, Stat5a was discovered as a mammary gland factor and indeed Stat5a 7/7 mice exhibit a profound defect in adult mammary gland development and lactogenesis . On the other hand, Stat5b 7/7 mice develop the defects related to the growth hormone actions (Udy et al, 1997). However, both types of the knockout mice additionally exhibit marked defects in the immune responses.…”