Sequence variation between the mouse and human glucose-6-phosphatase catalytic subunit gene promoters results in differential activation by peroxisome proliferator activated receptor gamma coactivator-1α

Schilling, Marcia M.; Oeser, James K.; Chandy, Joshua K.; Flemming, Brian P.; Allen, Shelley R.; O’Brien, Richard M.

doi:10.1007/s00125-008-1050-8

Cited by 12 publications

(7 citation statements)

References 48 publications

(83 reference statements)

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“…Interestingly, in the same year, HNF-4α was reported to mediate this activation by binding to the region between −76 and −64 of the mouse G6Pase promoter (Boustead et al 2003). In addition to the HNF-4α-binding site located between −76 and −64, a 3 bp sequence discovered by the same team was found to be a crucial site for HNF-4α-binding activity (Schilling et al 2008). In addition, many other transcription factors and coactivator proteins, such as DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), sterol regula tory element-binding proteins (SREBPs), vanin-1, cAMP, xenobiotic-metabolizing cytochrome P450 (CYP) 2A5 enzyme, HNF-6, and FOXO1, also contribute to the PGC-1α/HNF-4α-mediated transcriptional regulation of the gluconeogenic genes (Yamamoto et al 2004, Beaudry et al 2006, Arpiainen et al 2008, Schilling et al 2008, Nedumaran et al 2009, Dankel et al 2010.…”

Section: Hepatocyte Nuclear Factor-4αmentioning

confidence: 96%

PGC-1α, glucose metabolism and type 2 diabetes mellitus

Deng

Shi

et al. 2016

Journal of Endocrinology

125

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Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by glucose metabolic disturbance. A number of transcription factors and coactivators are involved in this process. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is an important transcription coactivator regulating cellular energy metabolism. Accumulating evidence has indicated that PGC-1α is involved in the regulation of T2DM. Therefore, a better understanding of the roles of PGC-1α may shed light on more efficient therapeutic strategies. Here, we review the most recent progress on PGC-1α and discuss its regulatory network in major glucose metabolic tissues such as the liver, skeletal muscle, pancreas and kidney. The significant associations between PGC-1α polymorphisms and T2DM are also discussed in this review.

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Section: Hepatocyte Nuclear Factor-4αmentioning

confidence: 96%

PGC-1α, glucose metabolism and type 2 diabetes mellitus

Deng

Shi

et al. 2016

Journal of Endocrinology

125

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“…Recent study has shown that insulin signaling stimulates S6/K1 kinase, which phosphorylates PGC-1a at Ser568 and Ser572 in hepatocytes, resulting in the loss of ability to interact with HNF4a (Lustig et al, 2011). PGC-1a seems to activate G6PC1 through the interaction with HNF4a-bound HNF4-binding site in mouse gene fairly well; however, this is not the case for human G6PC1 due to variation of nucleotide sequence adjacent to the HNF4a-binding site which markedly reduces PGC-1a-mediated transcriptional activation (Schilling et al, 2008).…”

Section: Peroxisome Proliferator-activated Receptor Coactivator-1amentioning

confidence: 90%

Insights into Transcriptional Regulation of Hepatic Glucose Production

Anyamaneeratch

Rojvirat

Sukjoi

et al. 2015

International Review of Cell and Molecular Biology

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“…Schilling and colleagues demonstrated that this species-specific difference could be explained by a 3 bp sequence variation, located immediately adjacent to a consensus nuclear hormone receptor half-site that is perfectly conserved between the mouse and human G6PC promoters. 43 With gel retardation experiments, Schilling and her colleagues demonstrated that this 3 bp variation in the human G6PC promoter extinguishes HNF-4α binding to the half-site. DHEA is a potent peroxisome proliferator and a known inducer of PGC-1α.…”

Section: Of Mice and Menmentioning

confidence: 99%

Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation

Nyce¹

2017

Transl Med Rep

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Glucose-6-phosphate dehydrogenase (G6PD) is an oncoprotein that is regulated by the p53 tumor suppressor. Mutant p53 loses the ability to inhibit G6PD, and loss of G6PD control clearly plays a role in oncogenesis. The steroid hormone precursor dehydroepiandrosterone (DHEA) is an endogenous uncompetitive inhibitor of G6PD. In humans, and a few other species, the sulfated circulatory form of DHEA (DHEAS) is present at extremely high concentrations -much higher than can be accounted for by DHEA's function as a precursor to steroid hormones. Uncompetitive inhibition is extremely rare in natural systems because it is irreversible in the presence of high concentrations of substrate and inhibitor. What has gone unappreciated is that such uncompetitive inhibition can quickly lead to cell death when the target is an obligatory housekeeping gene such as G6PD. Cells with inactivated p53 not only lose control over G6PD, but also over hexokinase (HK), the enzyme that converts glucose into glucose-6-phosphate (G6P), the substrate of G6PD. Furthermore, loss of p53 function de-represses NFκB activity, resulting in the upregulation of steroid sulfatase (SS) which converts circulating DHEAS into active DHEA. We propose that inactivation of p53 rapidly elevates G6P and DHEA concentrations in affected cells, driving uncompetitive inhibition of G6PD to lethal irreversibility. In animals with circulating DHEAS, this kill-switch mechanism may prevent most cases of p53 inactivation from becoming tumorigenic. Tumors would thus represent instances in which this mechanism had not been triggered, but which might still be triggered by application of DHEA sufficient to uncompetitively inhibit tumor G6PD. To test this hypothesis, we performed a pilot study in which dogs with cardiac hemangiosarcoma were treated with high dose (HD) DHEA supplemented with isoprene precursors to maintain geranylation of Rac GTPase. Tumor regression and longevity observed in these dogs supported the concept that some tumors retain extraordinary sensitivity to uncompetitive inhibition by DHEA.

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Sequence variation between the mouse and human glucose-6-phosphatase catalytic subunit gene promoters results in differential activation by peroxisome proliferator activated receptor gamma coactivator-1α

Abstract: Abstract

Cited by 12 publications

References 48 publications

PGC-1α, glucose metabolism and type 2 diabetes mellitus

PGC-1α, glucose metabolism and type 2 diabetes mellitus

Insights into Transcriptional Regulation of Hepatic Glucose Production

Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation

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