Coiled-coil Coactivators Play a Structural Role Mediating Interactions in Hypoxia-inducible Factor Heterodimerization

Guo, Yirui; Scheuermann, Thomas H.; Partch, Carrie L.; Tomchick, Diana R.; Gardner, Kevin H.

doi:10.1074/jbc.m114.632786

Cited by 30 publications

(27 citation statements)

References 37 publications

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“…The disparate outcomes observed here may indicate that tissue-selective contributions to HIF-2α regulation are dependent upon the local presence of one or more endogenous ligand(s). This paradigm establishes support for further investigation of cavities residing in each of the HIF PAS domains (41)(42)(43) as they too might contribute to the ability of HIFs to sense and respond to environmental and metabolic signals.…”

Section: Discussionmentioning

confidence: 60%

Modulation of HIF-2α PAS-B domain contributes to physiological responses

Feng

Zou

Chen

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Hypoxia-inducible factors (HIFs) are transcription factors in the basic helix–loop–helix PER-ARNT-SIM (bHLH-PAS) protein family that contain internal hydrophobic cavities within their PAS-A and PAS-B domains. Among HIFs, the HIF-2α PAS-B domain contains a relatively large cavity exploited for the development of specific artificial ligands such as PT2399. Administration of PT2399 could suppress HIF-2α target gene expression without affecting HIF-1 activity in mice under hypoxia conditions. A single mutation (S305M) within the HIF-2α PAS-B domain suppressed HIF-2α activity while conferring resistance to PT2399 in vivo, indicating the vital role of PAS-B domain in HIF-2α hypoxia response. In contrast, the mutant mice did not phenocopy PT2399 intervention in wild-type mice under metabolic stress. Under a high-fat diet (HFD), the mutant mice exert enhanced adipogenesis and obtain larger adipose mass and body weight gain compared to wild type. However, administration of PT2399 along with HFD feeding sufficiently suppressed HFD-induced body weight and adipose mass increase through suppression of adipogenesis and lipogenesis. The accompanying decreased lipid accumulation in the liver and improved glucose tolerance in wild-type mice were not observed in the mutant mice indicating negative regulation of HIF-2α on obesity and a complex role for the PAS-B domain in metabolic regulation. Notably, short-term administration of PT2399 to obese mice decreased adipose mass and improved metabolic condition. These results indicate a regulatory role for HIF-2α in obesity progression and suggest a therapeutic opportunity for PT2399 in obesity and associated metabolic disorders.

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Section: Discussionmentioning

confidence: 60%

Modulation of HIF-2α PAS-B domain contributes to physiological responses

Feng

Zou

Chen

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…One cannot exclude that the previously observed mode of interaction is relevant during the assembly of the complex or upon recruitment of associated factors. A binding site for coactivator TACC3 on the surface of ARNT PAS-B domain has also been described recently 28 , which is not fully accessible within our multi-domain structure (Extended Data Fig. 4d).…”

Section: Quaternary Architecture Of Hif-2a-arnt Heterodimermentioning

confidence: 69%

Structural integration in hypoxia-inducible factors

Potluri

et al. 2015

Nature

255

345

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The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-α and ARNT (also called HIF-1β) subunits. Here we describe crystal structures for each of mouse HIF-2α-ARNT and HIF-1α-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2α-ARNT and HIF-1α-ARNT, wherein ARNT spirals around the outside of each HIF-α subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-α mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.

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“…Smads require coactivators CBP1 and p300 for transcriptional activity [33]. One possible mechanism for inhibition of TGF-β-induced myofibroblast transformation may be hypoxia-induced HIF, which also requires the same coactivators [34], to bring about competition for CBP/p300 with Smads, thereby altering the TGF-β response.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Suppresses TGF-B1-Induced Cardiac Myocyte Myofibroblast Transformation by Inhibiting Smad2/3 and Rhoa Signaling Pathways

Yan

Shen

Liao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hypoxia modulation of transforming growth factor (TGF)- β-induced signaling during myofibroblast transformation is dependent on the specific cell type. The purpose of this study was to explore the effects of hypoxia on myofibroblast transformation of TGF-β1-induced cardiomyocyte H9c2 cells. Methods: H9c2 cells were cultured for intermittent hypoxia treatment and TGF-β1 treatment. α-Smooth muscle actin (α-SMA) expression was examined by western blotting and immunofluorescence after treatment. To further explore the possible mechanism for this effect, the effects of hypoxia on three early TGF-β-dependent signaling pathways, i.e. the Smad2/3, RhoA and mitogen-activated protein kinase (MAPK) pathways, were screened by western blotting. Results: Intermittent hypoxia induced TGF-β1 expression, but had no effect on α-SMA expression. Exogenous TGF-β1 alone upregulated α-SMA expression in H9c2 cells in a concentration- and time-dependent manner. α-SMA expression declined with the duration of hypoxia after intermittent hypoxia and exogenous TGF-β1 co-treatment. Phospho-JNK and phospho-p38 levels were not significantly altered after TGF-β1 and hypoxia treatment. However, levels of phospho-ERK increased after TGF-β1 treatment and continued to increase after hypoxia co-treatment. The activation of phospho-Smad2/3 and phospho-RhoA induced by TGFβ1 was significantly reduced after hypoxia co-treatment. Conclusion: Hypoxia can inhibit TGF-β1-induced H9c2 myofibroblast transformation, based on inhibition of α-SMA expression by suppressing signaling downstream of TGF-β1, Smad2/3 and RhoA. It suggested that TGF-β-mediated cardiomyocyte transformation is not involved in hypoxia-mediated fibrosis.

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Coiled-coil Coactivators Play a Structural Role Mediating Interactions in Hypoxia-inducible Factor Heterodimerization

Cited by 30 publications

References 37 publications

Modulation of HIF-2α PAS-B domain contributes to physiological responses

Modulation of HIF-2α PAS-B domain contributes to physiological responses

Structural integration in hypoxia-inducible factors

Hypoxia Suppresses TGF-B1-Induced Cardiac Myocyte Myofibroblast Transformation by Inhibiting Smad2/3 and Rhoa Signaling Pathways

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