Simultaneous, bidirectional inhibitory crosstalk between PPAR and STAT5b

Shipley, Jonathan; Waxman, David J.

doi:10.1016/j.taap.2003.12.020

Cited by 45 publications

(42 citation statements)

References 49 publications

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“…Bi-directional inhibitory cross-talk between STAT5 and oestrogen receptor-α [48,49], thyroid hormone receptor [24,50] and PPARα and PPARγ have been described [25,30,51]. In contrast with the present findings using HNF4α, however, the inhibition of STAT5 transcriptional activity by PPARs occurs at a step downstream from the JAK2-catalysed tyrosine phosphorylation step [25].…”

Section: Discussioncontrasting

confidence: 88%

“…We next investigated whether the inhibitory effect of HNF4α on STAT5b transcription is mutual, as reported for STAT5b and another nuclear receptor, PPAR [30]. To examine the effect of STAT5b on HNF4α-dependent transcription, we used a reporter gene based on ApoCIII, a well-established HNF4α target gene.…”

Section: Stimulatory Effect Of Stat5b On the Hnf4α-dependent Apociii mentioning

confidence: 99%

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Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Park

Wiwi

Waxman

2006

Biochemical Journal

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In the present study, we have characterized signalling cross-talk between STAT5b (signal transducer and activator of transcription 5b) and HNF4α (hepatocyte nuclear factor 4α), two major regulators of sex-dependent gene expression in the liver. In a HepG2 liver cell model, HNF4α strongly inhibited β-casein and ntcp (Na + /taurocholate cotransporting polypeptide) promoter activity stimulated by GH (growth hormone)-activated STAT5b, but had no effect on interferon-γ -stimulated STAT1 transcriptional activity. By contrast, STAT5b synergistically enhanced the transcriptional activity of HNF4α towards the ApoCIII (apolipoprotein CIII) promoter. The inhibitory effect of HNF4α on STAT5b transcription was associated with the inhibition of GH-stimulated STAT5b tyrosine phosphorylation and nuclear translocation. The short-chain fatty acid, butyrate, reversed STAT5b transcriptional inhibition by HNF4α, but did not reverse the inhibition of STAT5b tyrosine phosphorylation. HNF4α inhibition of STAT5b tyrosine phosphorylation was not reversed by pervanadate or by dominant-negative phosphotyrosine phosphatase 1B, suggesting that it does not result from an increase in STAT5b dephosphorylation. Rather, HNF4α blocked GHstimulated tyrosine phosphorylation of JAK2 (Janus kinase 2), a STAT5b tyrosine kinase. Thus STAT5b and HNF4α exhibit bidirectional cross-talk that may augment HNF4α-dependent gene transcription while inhibiting STAT5b transcriptional activity via the inhibitory effects of HNF4α on JAK2 phosphorylation, which leads to inhibition of STAT5b signalling initiated by the GH receptor at the cell surface.

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Section: Discussioncontrasting

confidence: 88%

Section: Stimulatory Effect Of Stat5b On the Hnf4α-dependent Apociii mentioning

confidence: 99%

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Park

Wiwi

Waxman

2006

Biochemical Journal

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“…Stat5A and 5B stimulated PPARg-induced adipogenesis and enhanced the transcriptional activity of PPARg, indicating that Stat5A and 5B stimulate adipogenesis by reinforcing the transcriptional activity of PPARg. In contrast to our results, Stat5A and 5B have been reported to inhibit the transcriptional activity of PPARg in COS1 and HEK293 cells (Richter et al 2003, Shipley & Waxman 2004. These results were repeatable in our hands (data not shown).…”

Section: Discussionsupporting

confidence: 64%

Growth hormone stimulates adipogenesis of 3T3-L1 cells through activation of the Stat5A/5B-PPARγ pathway

Kawai¹,

Namba²,

Mushiake³

et al. 2007

Journal of Molecular Endocrinology

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Growth hormone-deficient (GHD) patients show a decreased number of adipocytes, which is normalized by GH replacement, indicating an adipogenic effect of GH. However, the precise mechanisms underlying this effect remain to be clarified. In this study, we investigated the adipogenic effect of GH. GH stimulated MDI (3-isobutyl-1-methylxanthine, dexamethasone, and insulin)-induced adipogenesis of 3T3-L1 cells with early induction of peroxisome proliferator-activated receptors (PPAR)g2 expression. This adipogenic effect of GH was suppressed by overexpression of Stat5A mutant (Stat5A-Y694F), a transcriptional suppressor for the GH-Stat5A/5B signaling pathway, with the reduction of PPARg2 expression. Next, we investigated the relationship between Stat5A/5B and CCAAT/enhancer binding protein (C/EBP)b/d or PPARg in 3T3-L1 cells. Stat5A/5B stimulated C/EBPb-and C/EBPd-induced adipogenesis with enhancement of PPARg2 expression. In addition, Stat5A/5B enhanced the transcriptional activity of C/EBPb/d in the PPARg gene promoter. Furthermore, Stat5A/5B stimulated PPARg-induced adipogenesis and enhanced the transcriptional activity of PPARg. These results suggest that the GH-Stat5A/5B signaling pathway stimulates adipogenesis in cooperation with C/EBPb/d and PPARg. To completely understand the effect of GH, cDNA microarray analysis was performed to screen genes affected by GH during MDI-induced adipogenesis. Among 4277 genes, 18 and 19 genes were up-and down-regulated respectively. cDNA microarray analysis also indicated the up-regulation of PPARg and the modulation of expression of genes coding for growth factors or growth factor receptors, suggesting that GH stimulates adipogenesis in association with the modulation of cell growth. Thus, the GHStat5A/B signaling pathway stimulates adipogenesis through two distinct steps. In addition, cDNA microarray data provide us the further insights underlying the adipogenic effect of GH.

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“…It is important to note that Shipley and Waxman 44 have previously shown that GH-activated STAT5b can inhibit expression of ligand-activated PPAR␥ target genes, and vice versa, via a bi-directional posttranslational negative feedback loop. However, Rieusset et al 45 have reported that male PPAR␥ ϩ/Ϫ mice have reduced linear growth and weight gain and have shown that GH signaling is actually impaired in white adipose tissue of these mice, due to up-regulation of SOCS-2.…”

mentioning

confidence: 99%

Signal Transducer and Activator of Transcription 5b Promotes Mucosal Tolerance in Pediatric Crohn's Disease and Murine Colitis

Han

Osuntokun

Benight

et al. 2006

The American Journal of Pathology

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Growth hormone (GH) regulates anabolic metabolism via activation of the STAT5b transcription factor and reduces mucosal inflammation in colitis.Peroxisome proliferator-activated receptor (PPAR) ␥ suppresses mucosal inflammation and is regulated by GH through STAT5b. We hypothesized that the GH:STAT5b axis influences susceptibility to colitis via regulation of local PPAR␥ abundance. Colon biopsies from children with newly diagnosed Crohn's disease (CD) and controls were exposed to GH in short-term organ culture. Trinitrobenzene sulfonic acid (TNBS) administration was used to induce colitis in STAT5b-deficient mice and wildtype controls , with and without rosiglitazone pretreatment. GH receptor , STAT5b , PPAR␥ , and nuclear factor B activation and expression were determined. Epithelial cell GH receptor expression and GH-dependent STAT5b activation and PPAR␥ expression were reduced in CD colon. STAT5b-deficient mice exhibited reduced basal PPAR␥ nuclear abundance and developed more severe proximal colitis after TNBS administration. This was associated with a significant increase in mucosal nuclear factor B activation at baseline and after TNBS administration. Rosiglitazone ameliorated colitis in wild-type mice but not STAT5b-deficient mice. GHdependent STAT5b activation is impaired in affected CD colon and contributes to chronic mucosal inflammation via down-regulation of local PPAR␥ expression. Therapeutic activation of the GH:STAT5b axis therefore represents a novel target for restor- Current evidence suggests that Crohn's disease (CD) is caused by loss of tolerance to the enteric flora, leading to chronic inflammation and intestinal damage.1 Increased epithelial nuclear factor B (NF-B) activity and consequent chemokine expression are fundamental molecular features of this loss of tolerance. Increased NF-B DNAbinding activity has been attributed to increased binding of the p50 and p65 subunits.2 Importantly, disease activity in mice with colitis due to 2,4,6-trinitrobenzene sulfonic acid (TNBS) administration was inhibited by antisense oligonucleotides that inhibit p65 expression.2 These studies suggest a critical role for NF-B in mediating expression of proinflammatory factors, which are central to the pathogenesis of CD. Although much less is known regarding the regulatory transcription factors that may promote mucosal tolerance, recent studies have suggested that both STAT5a/b and peroxisome proliferator-activated receptor (PPAR) ␥ may play a role.Colonic mRNA expression of the STAT5b transcription factor is down-regulated in affected segments in adults with CD and ulcerative colitis.3 However, the functional significance of this is not known. Moreover, whether GHdependent STAT5b tyrosine phosphorylation and DNA binding are reduced in affected CD colon has not been determined. Current data suggest that the closely related STAT5a and STAT5b transcription factors are required, in

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Simultaneous, bidirectional inhibitory crosstalk between PPAR and STAT5b

Cited by 45 publications

References 49 publications

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Growth hormone stimulates adipogenesis of 3T3-L1 cells through activation of the Stat5A/5B-PPARγ pathway

Signal Transducer and Activator of Transcription 5b Promotes Mucosal Tolerance in Pediatric Crohn's Disease and Murine Colitis

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