Characterization of Distinct Stat5b Binding Sites That Mediate Growth Hormone-stimulated IGF-I Gene Transcription

Chia, Dennis J.; Ono, M.; Woelfle, Joachim; Schlesinger-Massart, Mylynda; Jiang, Honglin; Rotwein, Peter

doi:10.1074/jbc.m510204200

Cited by 80 publications

(73 citation statements)

References 46 publications

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“…The JAK2-STAT pathway is one of the major intracellular pathways in the IGF system that is frequently activated in various types of cancer cells [44,45]. Among a variety of STAT proteins, STAT5b directly regulates transcription of IGF-1 [34][35][36][37]. Moreover, expression of STAT5b was associated with tumor progression in human solid cancer [46][47][48].…”

Section: Discussionmentioning

confidence: 99%

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RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential in gastric cancer cells

et al. 2014

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Background ST6GalNAc I is a sialyltransferase controlling the expression of sialyl-Tn antigen (STn), which is overexpressed in several epithelial cancers, including gastric cancer, and is highly correlated with cancer metastasis. However, the functional contribution of ST6GalNAc I to development or progression of gastric cancer remains unclear. In this study, we investigated the effects of suppression of ST6GalNAc I on gastric cancer in vitro and in vivo. Methods Gastric cancer cell lines were transfected with ST6GalNAc I siRNA and were examined by cell proliferation, migration, and invasion assays. We also evaluated the effect of ST6GalNAc I siRNA treatment in a peritoneal dissemination mouse model. The differences in mRNA levels of selected signaling molecules were analyzed by polymerase chain reaction (PCR) arrays associated with tumor metastasis in MKN45 cells. The signal transducer and activator of transcription 5b (STAT5b) signaling pathways that reportedly regulate the insulin-like growth factor-1 (IGF-1) were analyzed by Western blot.

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Section: Discussionmentioning

confidence: 99%

“…To explore the molecular mechanisms by which ST6Gal-NAc I siRNA downregulates IGF-1 mRNA expression in MKN45 cells, we examined the STAT5b signaling pathways that reportedly regulate IGF-1 synthesis [34][35][36][37][38][39]. As Fig.…”

Section: Mechanism Of St6galnac I Sirna-induced Downregulation Of Igf-1mentioning

confidence: 99%

RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential in gastric cancer cells

et al. 2014

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“…This crosslinking reaction was stopped by addition of glycine to a final concentration of 0.125 M. The tissue was washed three times with ice-cold Dulbecco's phosphate-buffered saline containing 5 mM EDTA. The nuclei were subsequently isolated and lysed, and the ChIP procedure was performed as described previously (Chia et al, 2006). Briefly, the lysate was sonicated to generate DNA fragments with an average length of 100 to 1000 base pairs.…”

Section: Methodsmentioning

confidence: 99%

Attenuated Expression of Episodic Growth Hormone-Induced CYP2C11 in Female Rats Associated with Suboptimal Activation of the Jak2/Stat5B and Other Modulating Signaling Pathways

Dhir

Thangavel²,

Shapiro

2007

Drug Metab Dispos

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ABSTRACT:Inherent sex differences in various parameters of growth, musculoskeletal function, metabolism, and cytochrome P450 (P450)-dependent drug metabolism have been reported in rats and humans administered typical intermittent/episodic growth hormone (GH) replacement therapy. Having infused and monitored the identical physiologic masculine (episodic) growth hormone profile to both hypophysectomized male and female rats, we observed that induction levels of hepatic CYP2C11 were 35 to 40% lower in females. Associated with the reduced expression of the P450 isoform in the episodic GH-treated females were dramatically lower activation levels of Janus kinase (Jak2), signal transducers and activators of transcription (Stat5A and 5B) as well as 50% less binding of Stat5B to the CYP2C11 promoter. Because the Jak2/ Stat5B signaling pathway mediates the effects of the masculine GH profile on its target cells, we conclude that the lower induction level of CYP2C11 in females exposed to the masculine GH profile is probably due, at least in part, to the suboptimum activation of the Jak2/Stat5B pathway. In addition to the reduced activation of the Jak2/Stat5B pathway, we observed lower activational levels of mitogen-activated protein kinase (p44/p42) and, indirectly, nuclear factor-B in the episodic GH-treated females that may be involved in attenuating the activity of the Jak2/Stat5B pathway diminishing CYP2C11 expression levels.

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“…Indeed, IUGR children born small for gestational age have been described to have GH insufficiency, and current management of these small-for-gestational-age children who present with growth failure during childhood includes exogenous GH treatment (23). Alternatively, GH acts via the Jak/Stat pathway in which dimerized Stat proteins bind to GH responsive elements located in multiple sites on the IGF-1 gene to activate transcription (24). Perhaps these GH responsive elements are rendered inaccessible to Stat proteins due to a prenatal change in IGF-1 chromatin.…”

Section: Discussionmentioning

confidence: 99%

IUGR prevents IGF-1 upregulation in juvenile male mice by perturbing postnatal IGF-1 chromatin remodeling

Fung

Yang

et al. 2015

Pediatr Res

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Background: Intrauterine growth restriction (IUGR) offspring with rapid catch-up growth are at increased risk for early obesity especially in males. Persistent insulin-like growth factor-1 (IGF-1) reduction is an important risk factor. Using a mouse model of maternal hypertension-induced IUGR, we examined IGF-1 levels, promoter DNA methylation, and histone H3 covalent modifications at birth (D1). We additionally investigated whether prenatal perturbations could reset at preadolescence (D21). Methods: IUGR was induced via maternal thromboxane A 2 -analog infusion in mice. results: IUGR uniformly decreased D1 IGF-1 mRNA and protein levels with reduced promoter 1 (P1) transcription and increased P1 DNA methylation. IUGR males also had increased H3K4ac at exon 5 and 3′ distal UTR. At D21, IUGR males continued to have decreased IGF-1 levels, originating from both P1 and P2 with reduced 1A variant. IUGR males also had decreased activation mark of H3K4me3 at P1 compared with sham males. In contrast, D21 IUGR females normalized their IGF-1 levels, in association with an increased activation mark of H3K4me3 at P1 compared with sham females. conclusion: IUGR uniformly affected D1 hepatic IGF-1 epigenetic modifications in both sexes. However, at preadolescence, IUGR males are unable to correct for the prenatal reduction possibly due to a more perturbed IGF-1 chromatin structure.i ntrauterine growth restriction (IUGR) predisposes offspring toward early-onset metabolic syndrome. This predisposition is particularly pertinent with rapid postnatal catch-up growth and affects males more than females (1). The molecular mechanisms underlying this sex-specific predisposition remain elusive. Insulin-like growth factor 1 (IGF-1), a major regulator of growth and metabolism, has generated significant interest in the field (2). IGF-1 disruption has been implicated in aberrant growth and development of metabolic syndrome in both IUGR humans and animal models (3-6). In particular, decreased IGF-1 have been observed in IUGR humans who ultimately develop metabolic syndrome as adults (7,8).The IGF-1 gene is an ideal candidate to examine IUGR's effects not only because of its growth and metabolic properties but because of its complex gene structure allowing for developmental-and tissue-specific expression. The majority of serum IGF-1 is synthesized from the liver (9). The IGF-1 gene is regulated by two alternative promoters, promoter P1 initiates transcription from exon 1 while promoter P2 from exon 2. P1 is active in fetal life, whereas P2 becomes upregulated at ~3 wk of life when growth hormone exerts its effects on the rodent IGF-1 gene (10). The rodent IGF-1 gene also has an alternatively spliced exon, with the A variant excluding exon 5 and the B variant includes exon 5. Both alternative promoter selection and alternative exon splicing require specific epigenetic modifications to direct transcriptional machinery for specific mRNA transcript generation (11,12).Given that prenatal insults are known to affect gene-specific DNA methylation a...

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Characterization of Distinct Stat5b Binding Sites That Mediate Growth Hormone-stimulated IGF-I Gene Transcription

Cited by 80 publications

References 46 publications

RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential in gastric cancer cells

RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential in gastric cancer cells

Attenuated Expression of Episodic Growth Hormone-Induced CYP2C11 in Female Rats Associated with Suboptimal Activation of the Jak2/Stat5B and Other Modulating Signaling Pathways

IUGR prevents IGF-1 upregulation in juvenile male mice by perturbing postnatal IGF-1 chromatin remodeling

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