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

Park, Soo-Hee; Wiwi, Christopher A.; Waxman, David J.

doi:10.1042/bj20060332

Cited by 26 publications

(23 citation statements)

References 61 publications

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“…Sex differences in nuclear receptor-regulated liver metabolic pathways have been described (48), but their relationship to STAT5 action is obscure. A large fraction of sex-biased genes respond in parallel to the loss of STAT5 and HNF4A in male liver, indicating a codependence and suggesting that these two factors coregulate sexually dimorphic liver gene expression (27,28,46). Here, nuclear receptor motifs related most closely to those of HNF4A and the nuclear receptor PPAR were identified de novo as significantly enriched near STAT5 and BCL6 binding sites.…”

Section: Figmentioning

confidence: 83%

“…STAT5 and BCL6 have opposing effects on the transcriptional regulation of several GH response genes (6,7,43), suggesting that BCL6 might modulate the sex-biased effects of STAT5 on liver gene expression (43). Other transcription factors implicated in GH-dependent, sex-differential liver gene expression include the liver-enriched factors HNF4A and HNF6/ Onecut1 (4,14,28,33,46) and the homeobox CDP family member CUX2 (CUTL2) (35). However, it is not known whether these factors cooperate with STAT5 to regulate liver sex differences.…”

mentioning

confidence: 99%

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Dynamic, Sex-Differential STAT5 and BCL6 Binding to Sex-Biased, Growth Hormone-Regulated Genes in Adult Mouse Liver

Zhang

Laz

Waxman

2012

Molecular and Cellular Biology

145

261

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Sex-dependent pituitary growth hormone (GH) secretory patterns determine the sex-biased expression of >1,000 genes in mouse and rat liver, affecting lipid and drug metabolism, inflammation, and disease. A fundamental biological question is how robust differential expression can be achieved for hundreds of sex-biased genes simply based on the GH input signal pattern: pulsatile GH stimulation in males versus near-continuous GH exposure in females. STAT5 is an essential transcriptional mediator of the sex-dependent effects of GH in the liver, but the mechanisms that underlie its sex-dependent actions are obscure. Here we elucidate the dynamic, sex-dependent binding of STAT5 and the GH/STAT5-regulated repressor BCL6 to mouse liver chromatin genome wide, revealing a counteractive interplay between these two regulators of sex differences in liver gene expression. Our findings establish a close correlation between sex-dependent STAT5 binding and sex-biased target gene expression. Moreover, sex-dependent STAT5 binding correlated positively with sex-biased DNase hypersensitivity and H3-K4me1 and H3-K4me3 (activating) marks, correlated negatively with sex-biased H3-K27me3 (repressive) marks, and was associated with sexdifferentially enriched motifs for HNF6/CDP factors. Importantly, BCL6 binding was preferentially associated with repression of female-biased STAT5 targets in male liver. Furthermore, BCL6 and STAT5 common targets but not BCL6 unique targets showed strong enrichment for lipid and drug metabolism. These findings provide a comprehensive, genome-wide view of the mechanisms whereby these two GH-regulated transcription factors establish and maintain sex differences affecting liver physiology and disease. The approaches used here to characterize sex-dependent STAT5 and BCL6 binding can be applied to other condition-specific regulatory factors and binding sites and their interplay with cooperative chromatin binding factors.

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Section: Figmentioning

confidence: 83%

mentioning

confidence: 99%

Dynamic, Sex-Differential STAT5 and BCL6 Binding to Sex-Biased, Growth Hormone-Regulated Genes in Adult Mouse Liver

Zhang

Laz

Waxman

2012

Molecular and Cellular Biology

145

261

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“…The biological consequences obtained upon the loss of a single transcription factor are probably not only due to a loss-of-function but also due to a gainof-function by other recruited signaling pathways. In addition, because Stat5 interacts either directly or indirectly with other regulatory molecules, such as the glucocorticoid receptor 26 and the hepatocyte nuclear factor 4a, 27 loss of Stat5 might also affect biological responses initiated by these molecules. Thus, developmental and physiological changes observed upon the loss of a single transcription factor are likely the result of a greatly disturbed regulatory network.…”

Section: Molecular Networkmentioning

confidence: 99%

Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration

et al. 2007

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Growth hormone controls many facets of a cell's biology through the transcription factors Stat5a and Stat5b (Stat5). However, whole body deletion of these genes from the mouse does not provide portentous information on cell-specific cytokine signaling. To explore liver-specific functions of Stat5, the entire Stat5 locus was deleted in hepatocytes using Cre-mediated recombination. Notably, Stat5-mutant mice developed fatty livers and displayed impaired proliferation of hepatocytes upon partial hepatectomy (PHx). Loss of Stat5 led to molecular consequences beyond the reduced expression of Stat5 target genes, such as those encoding suppressor of cytokine signaling 2 (SOCS2), Cish, and insulin-like growth factor 1 (IGF-1). In particular, circulating growth hormone levels were increased and correlated with insulin resistance and increased insulin levels. Aberrant growth hormone (GH)-induced activation of the transcription factors Stat1 and Stat3 was observed in mutant livers. To test whether some of the defects observed in liver-specific Stat5 deficient mice were due to aberrant Stat1 expression and activation, we generated Stat1 ؊/؊ mice with a hepatocyte-specific deletion of Stat5. Mouse genetics has been employed to dissect the degree to which GH signals through its downstream mediators Stat5 and IGF-1. Inactivation of the GHR gene results in severe postnatal growth retardation, greatly decreased levels of IGF-1, and elevated levels of circulating GH. 1,2 The transcription factors Stat5a and Stat5b are highly conserved and serve overlapping and mostly redundant roles. However, pubertal growth of Stat5b Ϫ/Ϫ males, but not females, is reduced. 3,4 In contrast, normal body growth was observed in both Stat5a Ϫ/Ϫ males and females. 4,5 The complete deletion of the entire Stat5a/b locus resulted in perinatal lethality, 6 suggesting that Stat5 has a more important role than previously considered.It can be hypothesized that the loss of Stat5 will alter the physiology of a cell, because it also controls the transcription of genes encoding suppressor of cytokine signaling 2 (SOCS2) and SOCS3, which are negative regulators of cytokine signaling. Moreover, loss of Stat5 would result in vacant recruitment sites on receptors, which could lead to the activation of other STATs and their downstream targets. To further explore the complexity of the GHStat5 regulatory network in liver, we deleted the Stat5 locus specifically in hepatocytes using Cre-mediated re-

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“…Hepatocyte growth hormone receptors transduce pulsed hormone through a tyrosine phosphorylation cascade involving Jak2 and Stat5b. Activated Stat5b migrates to the nucleus and, in conjunction with recognized and unrecognized cofactors, enhances transcription of masculine genes while repressing feminine genes (9). In females, growth hormone is secreted at lower but more continuous levels from the pituitary, Stat5b remains unphosphorylated in the hepatocyte cytoplasm, and the default program of feminine transcription is maintained (7).…”

Section: Introductionmentioning

confidence: 99%

Hepatocellular Carcinoma Associated with Liver-Gender Disruption in Male Mice

Rogers

Theve²,

Feng³

et al. 2007

Cancer Research

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Hepatocellular carcinoma (HCC) is a male-predominant cancer associated with chronic hepatitis. Like human viral hepatitis, murine Helicobacter hepaticus infection produces inflammation and HCC with a masculine bias. We used this model to identify potential mechanisms of male HCC predisposition. Male weanling A/JCr mice (n = 67) were gavaged with H. hepaticus or vehicle. At 1 year, mice were distributed into four groups: surgical castration, chemical castration, castration followed by dihydrotestosterone supplementation, or sexually intact controls. Responses to infection were compared with IFN-; challenge alone. At 21 months, there was no significant difference in hepatitis between groups. Neither castration nor androgen receptor agonism altered tumor incidence. Infected mice with severe, but not mild, disease exhibited a mosaic of alterations to sexually dimorphic genes and microsomal long-chain fatty acids. By microarray, tumorigenic hepatitis was strongly associated with liver-gender disruption, defined as the loss of a gender-identifying hepatic molecular signature. IFN-; alone produced similar changes, demonstrating a role for proinflammatory cytokines in this process. In conclusion, hepatocarcinogenesis in male mice with chronic hepatitis is maturationally imprinted and androgen-independent. Proinflammatory cytokines may promote HCC in a malepredominant fashion due to high sensitivity of the masculinized liver to loss of sex-specific transcriptional balance. Liver-gender disruption has pleiotropic implications for hepatic enzyme activity, lipid processing, nuclear receptor activation, apoptosis, and proliferation. We propose a multistep model linking chronic hepatitis to liver cancer through cytokine-mediated derangement of gender-specific cellular metabolism. This model introduces a novel mechanism of inflammation-associated carcinogenesis consistent with male-predominant HCC risk. [Cancer Res 2007;67(24): 11536-46]

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

Cited by 26 publications

References 61 publications

Dynamic, Sex-Differential STAT5 and BCL6 Binding to Sex-Biased, Growth Hormone-Regulated Genes in Adult Mouse Liver

Dynamic, Sex-Differential STAT5 and BCL6 Binding to Sex-Biased, Growth Hormone-Regulated Genes in Adult Mouse Liver

Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration

Hepatocellular Carcinoma Associated with Liver-Gender Disruption in Male Mice

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