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STAT5b Is Required for GH-Induced Liver Igf-I Gene Expression

AgResearch (H.W.D., T.X., M.J.M.), Ruakura Research Centre, Hamilton 2001, New Zealand; Department of Biology (T.X., R.J.W.), University of Waikato, Hamilton 2001, New Zealand; Division of Cell and Molecular Biology (D.J.W.), Department of Biology, Boston University, Boston, Massachusetts 02215; and Department of Anatomy and Structural Biology (D.R.G.), School of Medical Sciences, University of Otago, Dunedin 6001, New Zealand

Address all correspondence and requests for reprints to: Helen W. Davey, AgResearch, Ruakura Research Center, East Street Private Bag 3123, Hamilton, New Zealand. E-mail: helen.davey{at}agresearch.co.nz

	Abstract

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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 theStat5b^-/- 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.

	Introduction

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THE EFFECTS OF GH on postnatal growth are mediated, at least in part, by the 70 amino acid peptide IGF-I, which is produced both in the liver (approximately 75% of total circulating IGF-I) and in peripheral tissues. Gene deletion studies have established that liver-derived IGF-I is dispensable for normal body growth, suggesting that IGF-I produced locally in peripheral tissues mediates the major effects of GH on postnatal growth (1, 2, 3, 4, 5, 6, 7) and that liver-derived IGF-I functions as a component of insulin action in peripheral tissues (8). However, the elevated plasma GH levels seen in liver IGF-I-deficient mice (8) may support growth via increased peripheral tissue expression of Igf-I, raising the possibility that liver-derived IGF-I may indeed help mediate the growth effects of GH under normal physiological conditions.

GH-stimulated dimerization of GH receptors on the cell surface of target tissues results in the activation of multiple intracellular signaling molecules, including MAP kinase, insulin receptor substrates, phosphoinositol 3'-phosphate kinase, diacylglycerol, PKC, intracellular calcium, and STAT signaling pathways (9, 10, 11). These intracellular factors mediate GH-stimulated changes in gene expression, and have diverse effects on growth and metabolism (11, 12, 13).

Although GH treatment of hypophysectomized rats induces Igf-I gene transcription within 30 min (14), the signaling pathways used by GH to activate Igf-I expression are unknown (11). One possibility is that GH-stimulated Igf-I expression is regulated by the JAK-STAT5b pathway, which we have shown to be required for sexually dimorphic body growth and also for the expression of the major urinary proteins and several cytochrome P450 enzymes in murine liver (15, 16). These well characterized gender differences in body growth and gene expression are particularly striking in rodents and result from the distinct temporal patterns of pituitary GH secretion that occur in males and females (17).

The availability of mice that are deficient in STAT5b has provided a simple in vivo model to test the hypothesis that GH-induced Igf-I expression is dependent on STAT5b signaling. In the present study, wild-type (WT) and Stat5b^-/- male mice were hypophysectomized to eliminate endogenous GH, and then GH was replaced by injections given twice daily. Expression of Igf-I mRNA was stimulated by GH in livers of WT, but not Stat5b^-/- mice, providing strong evidence for the involvement of STAT5b in GH-induced liver Igf-I gene expression.

	Materials and Methods

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Animals
Male 129 X BALB/c WT and Stat5b^-/- mice were hypophysectomized by the parapharyngeal route (18) at 4–17 wk of age and maintained on a 12-h light, 12-h dark schedule, with free access to food and drinking water (supplemented with 5% glucose wt/vol) for 8 wk. Bovine GH (2 µg per g body weight; American Cyanamid Co., Princeton, NJ) was then injected ip at 12-h intervals for 7 d. This protocol has previously been shown to reestablish male-specific gene expression patterns in GH-deficient mice (16, 19). No thyroxine was given before or during this experiment, although some mice had been treated for 1 wk for an independent experiment to measure major urinary protein expression (16), at least 2 wk before the GH treatment. There was no glucocorticoid replacement at any time. Liver tissue from 3-month-old intact male and female WT and Stat5b^-/- mice was also analyzed. Mice were killed by CO₂ asphyxiation (at similar times after GH injection for both WT and Stat5b^-/- mice), and livers were collected and frozen in liquid nitrogen. The experimental procedures were approved by the Ruakura Animal Ethics Committee acting in accordance with the guidelines of the New Zealand Animal Ethics Advisory Committee.

RNA isolation, Northern analysis, and quantitative PCR
Total RNA was extracted using TRIZOL (Life Technologies, Inc.). The RNA (15 µg) was fractionated on a 1% formaldehyde-agarose gel, then transferred and fixed to Hybond N⁺ (Amersham Pharmacia Biotech). cDNA probes were labeled with [-³²P]dCTP (Rediprime II labeling kit, Amersham Pharmacia Biotech). For Igf-I (ovine Igf-I cDNA, provided by Dr. E. A. Wong, Virginia Polytechnic Institute and State University), the hybridization was at 60 C for 7 h (20), and the membrane was washed at 60 C to 0.5x SSC, 0.1% SDS. For probings for expression of GH receptor (ovine Ghr cDNA provided by Dr. T. E. Adams, CSIRO, Parkville, Australia), Cis (mouse cDNA provided by Dr. D. J. Hilton, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia) and ß actin (21), the Super Hyb kit was used (Molecular Research Center, Inc., Cincinnati, OH). Membranes were exposed to X-OMAT AR film with an intensifying screen at -80 C.

In addition to Northern analyses, we used the ABI Prism 7700 Sequence Detection System (Applied Biosystems) to quantify relative levels of gene expression. TaqMan probes and primers were designed for murine Igf-I, GH receptor (Ghr) and glyceraldehyde-3-phosphate dehydrogenase (Gapdh) mRNA transcripts, and were used to measure the relative amounts of these mRNAs in liver tissue by real-time quantitative RT-PCR. To detect Igf-I transcripts, the probe and primers were designed to detect exons 3 and 4, which are common to all Igf-I mRNAs (22, 23) (mIgf-I probe 5' CTC CAG CAT TCG GAG GGC ACC TC 3'; forward primer 5' CTT CAA CAA GCC CAC AGG CTA T 3'; reverse primer 5' GCT CCG GAA GCA ACA CTC AT 3'). For GH receptor mRNA, the primers and probe were designed to detect exons 7 and 8 (mGhr-probe 5' CAC ATG CTT CCA ATA TGT TCG TCT GAG GAA 3'; forward primer 5' TTC AGC GAA GTC CTC CGT GTA 3'; reverse primer 5' AGA ACC ATG GAA ACT GGA TAT CTT CT 3'). GH binding protein mRNA, which is derived from splicing of an alternative 8A exon (24, 25) is not amplified using these primers, and genomic DNA sequences are not amplified efficiently because the primers span intron sequences. Reverse transcriptase (Superscript II, Life Technologies, Inc.) was used to synthesize cDNA before PCR. Control reactions without reverse transcriptase were included in the assays to ensure that DNA, including pseudogene sequences, did not contribute to the quantification results. Gapdh was used to normalize differences in the amounts of template RNA used in the TaqMan assays (mGapdh probe 5'-TGG AAG GGC TCA TGA CCA CAG TCC A-3'; Forward primer 5' TGC ACC ACC AAC TGC TTA GC 3'; Reverse primer 5' GTC TTC TGG GTG GCA GTG ATG 3'). Universal PCR Master Mix (PE Applied Biosystems) was used in these studies. The concentration of primers and probe were 300 nM and 200 nM, respectively. The PCR program was 50 C for 2 min; 95 C for 10 min; then 40 cycles of 95 C for 15 sec and 60 C for 1 min.

The relative amounts of mRNA were calculated from the threshold cycle numbers, and are presented relative to the amounts of mRNA in one sample that is arbitrarily set at one. The threshold cycle is the first PCR cycle for which there is a statistically significant increase in fluorescence resulting from the 5' nuclease activity of the AmpliTaq Gold DNA polymerase. The fluorescence increases exponentially with the amount of PCR product and the threshold cycle reflects the amount of target RNA or DNA in the sample (i.e. more target results in a lower threshold cycle). The threshold cycle for Gapdh was used to standardize the amount of sample RNA in the reaction i.e. the difference in the threshold cycles for Igf-I or Ghr and Gapdh mRNA was used to calculate the relative amounts of Igf-I or Ghr mRNAs in each sample.

Serum IGF-1 assay
Mouse serum IGF-I concentrations were measured after acid-ethanol cryoprecipitation using a RIA, as previously described (26).

Statistical analysis
Serum IGF-I concentrations were analyzed by ANOVA of the log transformed concentrations, using Minitab Release 12 (Minitab Inc., State College, PA). The results are presented as the backtransformed geometric means.

TaqMan mRNA data are presented as the means and SEMs. The PCR threshold cycle differences were transformed using 2^value to determine the relative levels of mRNA expression (because there is a 2-fold exponential increase in the amount of DNA product/fluorescence following each PCR cycle). Levels of significance were calculated by ANOVA using Minitab Release 12. t tests were also used to make comparisons between two groups where appropriate.

	Results

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Completeness of hypophysectomy
Several criteria were used to confirm that the pituitaries were successfully removed. These included a marked reduction in the excretion of major urinary proteins in urine (measured 2 and 8 wk following surgery), low serum PRL concentrations, the absence of the pituitaries on post mortem inspection of the base of the skull, and the absence of body growth (18) (data not shown). Following hypophysectomy, the body weights of the mice did not increase; even young mice that weighed about 15 g remained at this weight. A few of the older mice (>30 g) lost weight immediately following hypophysectomy, but there was no apparent difference between WT and Stat5b^-/- mice.

Liver Igf-I mRNA is induced by GH in hypophysectomized WT but not hypophysectomized Stat5b^-/- mice.
The levels of Igf-I mRNA in the livers of intact male and female WT and Stat5b^-/- mice, and in male hypophysectomized WT and Stat5b^-/-mice either with or without GH replacement were determined using real-time quantitative PCR (Fig. 1A) and Northern blot analysis (Fig. 1B). STAT5b deficiency, in itself, resulted in a 50% reduction (P < 0.01, t test) in the average Igf-I mRNA in the liver (Fig. 1A). Following hypophysectomy, the levels of Igf-I dropped dramatically, in both WT and Stat5b^-/-male mice, to 8% and 1.3% of the levels found in intact WT mice. GH injection twice daily for 7 d induced the expression of Igf-I mRNA in hypophysectomized WT mice to levels that were similar to the intact WT mice. By contrast, in hypophysectomized Stat5b^-/- mice there was no significant increase in liver Igf-I mRNA in response to GH (Fig. 1A).

View larger version (42K): [in this window] [in a new window]   Figure 1. A, Relative levels of Igf-I mRNA in livers of WT and Stat5b-/- (knockout; KO) mice, and in hypophysectomized (Hx) male mice that were untreated (-) or injected with bGH (+) every 12 h for 7 d as described under Materials and Methods. TaqMan real-time RT-PCR was used to quantify the indicated mRNAs in six to nine mice per group. The mRNA levels reported are normalized to Gapdh mRNA levels, and are expressed relative to the level in untreated hypophysectomized male Stat5b-/- mice. Differences between the means in the ANOVA, are indicated by letters. a and b differ from d (P < 0.001); a differs from c (P < 0.05). In separate analyses using t test, Igf-I mRNA was found to be higher (P < 0.01) in both male and female intact WT vs. intact Stat5b-/- mice. B, Northern blot analysis of Igf-I mRNA in individual hypophysectomized male mice. Total RNA (15 µg) was separated on a 1% agarose gel, transferred to a nylon membrane and probed with radioactively labeled cDNA probe. The Igf-I cDNA hybridized to mRNA transcripts of 0.9–1.2, 1.5–1.9, and 7.0–7.5 kb. C, The ethidium bromide stained agarose gel before northern blotting, showing the consistency of the 28S and 18S rRNAs.

Serum IGF-I levels follow similar trends to liver mRNA levels
Stat5b^-/- mice have about 30% lower levels of serum IGF-I compared with WT mice (15). As expected, hypophysectomy greatly reduced serum IGF-I levels in both WT and Stat5b^-/- mice (Table 1). Pulsatile GH replacement for 7 d stimulated a dramatic 13-fold increase in serum IGF-I in hypophysectomized WT mice (P < 0.001). By contrast, in hypophysectomized Stat5b^-/- mice, GH replacement stimulated a very small increase in serum IGF-I (P < 0.05) (Table 1). The GH-induced IGF-I level in hypophysectomized WT mice, corresponds to a 79% restoration of the IGF-I levels that we previously reported in WT intact mice (15).

View larger version (48K): [in this window] [in a new window]   Figure 2. A, Relative levels of Ghr mRNA in livers of WT (WT) and Stat5b-/- (KO) mice and in hypophysectomized (Hx) male mice that were untreated (-) or treated for 7 d with GH (+) as described in Materials and Methods. TaqMan real-time RT-PCR was used to quantify the indicated mRNAs in six to nine mice per group. The mRNA levels reported are normalized to Gapdh mRNA levels and are expressed relative to the level in untreated hypophysectomized male Stat5b-/- mice. Differences between the means are indicated by letters. a differs from b (P < 0.01). B, GH receptor mRNA in individual hypophysectomized male WT (WT) and Stat5b-/- (KO) mice. Total RNA (15 µg) was electrophoresed on a 1% denaturing agarose gel, transferred to nylon membrane and hybridized with radiolabeled Ghr cDNA. The membrane was exposed to X-OMAT-AR film. C, Northern blot from B, stripped and reprobed with a human ß actin cDNA probe.

View larger version (32K): [in this window] [in a new window]   Figure 3. Cis mRNA in individual hypophysectomized male WT and Stat5b-/- (KO) mice. Total RNA (15 µg) was electrophoresed on a 1% denaturing agarose gel, transferred to nylon membrane and hybridized with radiolabeled Cis cDNA. The membrane was exposed to X-OMAT-AR film.

	Discussion

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GH rapidly and transiently stimulates transcription of Igf-I in liver in vivo (14, 29) and activates a number of intracellular signaling pathways (11, 13) including those mediated by STATs 1, 3, 5a, and 5b (9, 10, 30, 31, 32). However, the relative importance of these events for GH-induced Igf-I gene expression was not previously resolved by these, or other, experiments (33, 34). Serum IGF-I levels are dramatically reduced in hypophysectomized rats, to about 5% of those found in intact rats, and these low basal levels have facilitated studies of the kinetics of GH-induced Igf-I expression. Using this model, a single injection of GH increases Igf-I transcription within 30 min (14). In the present study, we also used hypophysectomy to eliminate endogenous GH and circulating IGF-I. The induction of liver Igf-I mRNA in WT, but not in Stat5b^-/- mice following GH replacement provides a simple demonstration of the requirement for STAT5b in the GH-induced expression of Igf-I in hypophysectomized mice. This requirement of STAT5b for GH pulse stimulation of Igf-I (this study) and male-specific liver cytochrome P450s seen earlier (16) does not reflect a generalized loss of GH signaling, as evidenced by the GH-inducible expression of Cis mRNA in the same mice (Fig. 3).

The present demonstration that STAT5b plays a role in liver Igf-I expression raises several questions. The average level of liver Igf-I mRNA in intact Stat5b^-/- mice was 50% of that in WT mice, which is in agreement with our finding that Stat5b^-/- mice have serum IGF-I levels that are approximately 30% lower than WT mice (15). This result would not be predicted, however, if the sole signaling pathway for expressing Igf-I was via GH activation of STAT5b. The dramatic reduction in serum IGF-I levels seen in hypophysectomized Stat5b^-/- mice (Table 1) indicates that factors secreted by or regulated by the pituitary gland play an important role in maintaining serum IGF-I in a STAT5b-independent manner. That GH is primarily responsible for Igf-I expression is indicated by the near complete restoration of serum IGF-I in response to GH treatment of WT hypophysectomized mice. One possible explanation for these observations is that compensatory mechanisms, involving pituitary-derived factors other than GH, operate in intact but not hypophysectomized Stat5b^-/- mice, resulting in substantial expression of Igf-I in liver, and consequently maintenance of plasma levels of IGF-I despite the absence of STAT5b. There is also indirect evidence that pituitary GH secretion may be elevated in Stat5b^-/- mice (15, 35), which may stimulate Igf-I expression in peripheral tissues by a STAT5b-independent pathway perhaps involving STAT5a.

A further question is whether GH acts directly to activate Igf-I gene expression via the JAK-STAT5b pathway, or whether GH-activated STAT5b operates via an indirect mechanism to induce Igf-I gene expression. GH has an immediate effect on Igf-I gene transcription in WT hypophysectomized rats (14). However, whereas there may be a direct action of GH on Igf-I transcription in the present experiments, the STAT5b requirement for Igf-I expression may nevertheless be an indirect one, i.e. STAT5b may not directly activate Igf-I gene transcription by directly binding to the promoter or interacting in transcription complexes. STAT5 DNA-binding consensus elements have not been identified in rodent Igf-I 5' flanking DNA sequences, but the analysis has not been extensive. Moreover, STAT5 tetramers have the ability to bind to adjacent weak consensus elements that are not revealed in a search for standard STAT5 consensus sequences (36). Further investigation, including a more detailed analysis of Igf-I gene regulatory elements, and a determination of whether a single pulse of GH stimulates a rapid increase in Igf-I mRNA in hypophysectomized WT but not Stat5b^-/- mice, will be required to establish the precise role of the STAT5b pathway in GH-induced liver Igf-I gene expression.

Also of interest is whether STAT5b is specifically required for Igf-I gene expression, or whether STAT5a, which shares 92% amino acid identity with STAT5b, acts equivalently in this regard. Greater than 90% of the Stat5 mRNA in liver is Stat5b (37), and thus Stat5b^-/- mice are estimated to have dramatically lower levels of STAT5 per se than WT mice. Liver STAT5a protein levels are not altered by Stat5b gene disruption or by hypophysectomy of the Stat5b^-/- mice (16) and because the pattern of STAT5a activation in the liver is similar to that for STAT5b (37, 38), the reduced amounts of total STAT5 protein, rather than the loss of STAT5b per se, could explain the lack of GH-induced Igf-I mRNA in the livers of hypophysectomized Stat5b^-/- mice.

GH treatment of hypophysectomized Stat5b^-/- mice stimulated a modest increase in serum IGF-I levels (P < 0.05), which was greater than the increase in liver Igf-I mRNA levels. This proportionally greater increase in serum IGF-I may reflect changes in extrahepatic IGF-I production, as well as changes in other GH-regulated factors that modulate plasma IGF-I, such as IGFBP3 and the acid labile subunit ALS (39), that may, at least in part, be independent of STAT5b. Alternatively, as in intact Stat5b^-/- mice, a portion of serum IGF-I may be derived from GH-JAK2 signaling mediated by STAT5a, which is activated in hypophysectomized Stat5b^-/- mice by GH treatment (16). This latter observation, together with the induction of Cis expression in the livers of GH-treated hypophysectomized Stat5b^-/- mice noted above, provides clear evidence for a functional GH receptor/JAK2 pathway in these mice. Accordingly, defects in these components can be ruled out as the basis for the unresponsiveness of the Igf-I gene (Fig. 1) and the sexually dimorphic liver cytochrome P450s (16), to GH pulse stimulation in Stat5b^-/- mice.

In conclusion, our data provides strong evidence for STAT5b playing an important role in liver Igf-I expression.

	Acknowledgments

 
We thank Dr. P. K. Lund (University of North Carolina at Chapel Hill) for encouraging us to do this work, Dr. B. H. Breier (University of Auckland) for performing the IGF-I assays and Simrana Clayton for the technical assistance. We also thank American Cyanamid Co. for providing the bGH. Special thanks to Ric Broadhurst for assistance with anesthesia and surgery, Glenda Smith and Bobby Smith for care of the mice, and Harold Henderson for statistical advice.

	Footnotes

 
This work was funded by the New Zealand Marsden Fund (H.W.D., R.J.W.) and by the U.S. National Institutes of Health, Grant DK-33765 (D.J.W.)

Abbreviations: Hx, Hypophysectomized; KO, knockout; WT, wild-type.

Received February 15, 2001.

Accepted for publication May 31, 2001.

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