The role of growth hormone in α2u globulin synthesis: A reexamination

Lynch, Kevin R.; Dolan, Kevin P.; Nakhasi, Hira L.; Unterman, Ronald D.; Feigelson, Philip

doi:10.1016/0092-8674(82)90388-9

Cited by 57 publications

(17 citation statements)

References 16 publications

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“…The effects of hypophysectomy and GH pulse replacement on body growth and liver gene expression obtained in wild-type mice were in full agreement with earlier reports (1,25,(35)(36)(37). First, there was no increase in the body weights of any of the mice following hypophysectomy.…”

Section: Figsupporting

confidence: 80%

STAT5b-deficient Mice Are Growth Hormone Pulse-resistant

Davey¹,

Park²,

Grattan³

et al. 1999

Journal of Biological Chemistry

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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...

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Section: Figsupporting

confidence: 80%

STAT5b-deficient Mice Are Growth Hormone Pulse-resistant

Davey¹,

Park²,

Grattan³

et al. 1999

Journal of Biological Chemistry

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“…The MUPs of the mouse are homologous to the rat urinary protein, a2.-globulin (18). a2.-Globulin is also encoded by a multigene family of approximately 20 genes (21) and has been shown to be subject to multihormonal regulation in the liver by growth hormone, thyroxine, testosterone, and glucocorticoid hormones (22,23,25,29,30 There are a number of apparent differences in hormonal regulation between the murine and rat proteins. It is not clear whether a2.-globulin is subject to differential hormonal regulation, as indicated by the results presented here.…”

Section: Resultsmentioning

confidence: 99%

“…The arrows indicate the position of MUP 3 (see Fig. 2 (22,25,29,30). To examine the effect of growth hormone on MUP mRNA levels, we utilized the mutant mouse strain little (4,13 However, RNA derived from the livers of male little mice treated with growth hormone directed the synthesis of normal male levels of MUP.…”

Section: Resultsmentioning

confidence: 99%

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Differential, multihormonal regulation of the mouse major urinary protein gene family in the liver.

Knopf¹,

Gallagher²,

Held³

1983

Mol. Cell. Biol.

125

131

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The hormonal requirements for the regulation of the major urinary protein (MUP) mRNA levels in mouse liver have been examined. Previous experiments have shown that administration of testosterone to female or castrated male mice increases MUP mRNA levels approximately fivefold to normal male levels. We have found that thyroxine and the peptide hormone, growth hormone, each had a pronounced effect on MUP mRNA levels. MUP mRNA was reduced 150-fold in growth-hormone-deficient mutant mice (little). The administration of growth hormone and thyroxine induced MUP mRNA approximately 150-fold, and when administered together, they induced MUP mRNA approximately 1,000-fold. testosterone administration. When administered separately to these mice, growth hormone and thyroxine induced with MUP mRNA approximately 150-fold, and when administered together, they induced MUP mRNA approximately 1,000-fold. Testicular feminized mice, which lack a functional major testosterone receptor protein, can also be induced to male levels by treatment with both growth hormone and thyroxine. In addition, we present evidence which indicates that growth hormone, thyroxine, and testosterone differentially regulate the levels of distinct MUP mRNA species.The major urinary proteins (MUPs) of mice were originally described as a group of antigenically related low-molecular-weight acidic proteins synthesized in the liver, secreted into the serum, and ultimately excreted in the urine (14-16). A homologous protein, a2.-globulin, has been described in rats (24,31,32). More recently, hybridization experiments have shown that the MUPs constitute a multigene family of 20 to 30 genes (7,18). Genetic mapping studies with recombinant inbred mice and mouse-hamster hybrid cell lines indicate that the MUP structural genes are clustered on chromosome 4 (5, 7, 20).Although the liver appears to be the major site of MUP synthesis, recent studies have shown that the MUP gene family is expressed in several secretory tissues of mice (18,34). The tissues expressing MUP mRNA sequences are the liver, the submaxillary gland, the lachrymal gland, and the mammary gland. These studies also indicated that expression of MUP mRNA in each of the tissues is under different developmental and hormonal controls (34).Early studies on the regulation of the MUPs examined the urinary levels of those proteins whose major site of synthesis appears to be the liver (36; this paper). Parfentjer (28) ed that male mice exhibit high levels of proteinuria and that the onset of this proteinuria correlated with the onset of sexual maturity. The role of the major male sex steroid, testosterone, was further indicated by demonstrating that either females or castrated males treated with testosterone attain normal male levels of proteinuria (38). Biochemical examination of these urinary proteins by Finlayson et al. (16) revealed a group of low-molecular-weight acidic proteins which exhibit both strain-and sex-specific electrophoretically distinguishable phenotypes (14, 37). Interestingly, these studies a...

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“…a2u globulins were first discovered because they were synthesized at high levels in the livers of male but not female rats and excreted in large quantity in the urine (16,47,48). Numerous studies have established that the synthesis of a2u globulin in the liver is regulated by a variety of hormones, including androgens, estrogens, glucocorticoids, growth hormone, and thyroxine (7,15,30,32,33,35,(43)(44)(45)(46)52), and regulation appears to occur primarily at the level of transcription (26). a2u globulins are also synthesized in several secretory tissues, such as the submaxillary, lachrymal, mammary, and preputial glands.…”

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confidence: 99%

Tissue-specific and hormonally regulated expression of a rat alpha 2u globulin gene in transgenic mice.

Soares¹,

Gubits²,

Feigelson³

et al. 1987

Mol. Cell. Biol.

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To investigate the tissue-specific and hormonal regulation of the rat a2. globulin gene family, we introduced one cloned member of the gene family into the mouse germ line and studied its expression in the resulting transgenic mice. a2u globulin gene 207 was microinjected on a 7-kilobase DNA fragment, and four transgenic lines were analyzed. The transgene was expressed at very high levels, specifically in the liver and the preputial gland of adult male mice. The expression in male liver was first detected at puberty, and no expression was detected in female transgenic mice. This pattern of expression is similar to the expression of endogenous a2u globulin genes in the rat but differs from the expression of the homologous mouse major urinary protein (MUP) gene family in that MUPs are synthesized in female liver and not in the male preputial gland. We conclude that these differences between rat a2u globulin and mouse MUP gene expression are due to evolutionary differences in cis-acting regulatory elements. The expression of the a2u globulin transgene in the liver was abolished by castration and fully restored after testosterone replacement. The expression could also be induced in the livers of female mice by treatment with either testosterone or dexamethasone, following ovariectomy and adrenalectomy. Therefore, the cis-acting elements responsible for regulation by these two hormones, as well as those responsible for tissue-specific expression, are closely linked to the U2. globulin gene.

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The role of growth hormone in α2u globulin synthesis: A reexamination

Cited by 57 publications

References 16 publications

STAT5b-deficient Mice Are Growth Hormone Pulse-resistant

STAT5b-deficient Mice Are Growth Hormone Pulse-resistant

Differential, multihormonal regulation of the mouse major urinary protein gene family in the liver.

Tissue-specific and hormonally regulated expression of a rat alpha 2u globulin gene in transgenic mice.

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