Nur77 upregulates HIF-α by inhibiting pVHL-mediated degradation

Kim, Bu Yeon; Kim, Hyungsoo; Cho, Eun Jung; Youn, Hong Duk

doi:10.3858/emm.2008.40.1.71

Cited by 35 publications

(34 citation statements)

References 39 publications

(53 reference statements)

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“…4,5,[29][30][31][32][33] Moreover, some bcl-2 protein interactors, such as the bcl-2 mitochondrial chaperone FKBP38, the orphan nuclear receptor Nur77 and the molecular chaperone HSP90, have been demonstrated to be involved in oxygen-dependent and -independent regulation of the HIF-1a protein. [33][34][35] Even if we recently demonstrated that bcl-2 protein under hypoxic conditions interacts with both HIF-1a and HSP90 proteins contributing to the enhancement of HIF-1a protein stability, 21 we cannot exclude that also other bcl-2 interactors can be involved in bcl-2-induced HIF-1a/VEGF regulation.…”

Section: Discussionmentioning

confidence: 94%

Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

Trisciuoglio¹,

Gabellini

Desideri³

et al. 2011

Cell Death Differ

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In addition to act as an antiapoptotic protein, B-cell lymphoma (bcl)-2 can also promote tumor angiogenesis. In this context, we have previously demonstrated that under hypoxia bcl-2 promotes hypoxia-inducible factor-1 (HIF-1)-mediated vascular endothelial growth factor (VEGF) expression in melanoma and breast carcinoma. Here, we report on the role of the BH4 domain in bcl-2 functions, by showing that removal of or mutations at the BH4 domain abrogate the ability of bcl-2 to induce VEGF protein expression and transcriptional activity under hypoxia in human melanoma cells. We have also extended this observation to other human tumor histotypes, such as colon, ovarian and lung carcinomas. The involvement of BH4 on HIF-1a protein expression, stability, ubiquitination and HIF-1 transcriptional activity was also demonstrated in melanoma experimental model. Moreover, we validated the role of the BH4 domain of bcl-2 in the regulation of HIF-1/VEGF axis, demonstrating that BH4 peptide is sufficient to increase HIF-1a protein half-life impairing HIF-1a protein ubiquitination, and to enhance VEGF secretion in melanoma cells exposed to hypoxia. Finally, we found that the mechanism by which bcl-2 regulates HIF-1-mediated VEGF expression does not require BH1 and BH2 domains, and it is independent of antiapoptotic and prosurvival function of bcl-2.

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Section: Discussionmentioning

confidence: 94%

Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

Trisciuoglio¹,

Gabellini

Desideri³

et al. 2011

Cell Death Differ

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“…Ubiquitination of HIF-1α is mediated by interaction with von Hippel-Lindau tumor suppressor protein (pVHL) (Kim et al, 2008). HIF-1α is targeted for VHL E3 ligase complex by proline hydroxylation of oxygen-dependent degradation (ODD) domain (Semenza, 2001;Safran and Kaelin, 2003).…”

Section: Introductionmentioning

confidence: 99%

STAT3 inhibits the degradation of HIF-1α by pVHL-mediated ubiquitination

et al. 2008

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Abbreviations: HIF-1α, hypoxia inducible factor-1α; STAT3, signal transducer and activator of transcription 3; VHL, von Hippel-Lindau Abstract Hypoxia-inducible factor 1α (HIF-1α) is rapidly degraded by the ubiquitin-proteasome pathway under normoxic conditions. Ubiquitination of HIF-1α is mediated by interaction with von Hippel-Lindau tumor suppressor protein (pVHL). In our previous report, we found that hypoxia-induced active signal transducer and activator of transcription3 (STAT3) accelerated the accumulation of HIF-1α protein and prolonged its half-life in solid tumor cells. However, its specific mechanisms are not fully understood. Thus, we examined the role of STAT3 in the mechanism of pVHL-mediated HIF-1α stability. We found that STAT3 interacts with C-terminal domain of HIF-1α and stabilizes HIF-1α by inhibition of pVHL binding to HIF-1α. The binding between HIF-1α and pVHL, negative regulator of HIF-1α stability, was interfered dose-dependently by overexpressed constitutive active STAT3. Moreover, we found that the enhanced HIF-1α protein levels by active STAT3 are due to decrease of poly-ubiquitination of HIF-1α protein via inhibition of interaction between pVHL and HIF-1α. Taken together, our results suggest that STAT3 decreases the pVHL-mediated ubiquitination of HIF-1α through competition with pVHL for binding to HIF-1 α, and then stabilizes HIF-1α protein levels.

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“…Another important non-genomic function of NR4A1 appears to be the stabilization of hypoxia-inducible factor-1a (HIF-1a) under non-hypoxic conditions [56]. In normoxia, the a subunit of transcription factor HIF-1 becomes rapidly degraded through the ubiquitin-proteasome pathway [57].…”

Section: Nr4a1 As a Regulator Of Protein Stabilitymentioning

confidence: 99%

“…(as well as NR4A2) has the ability to bind the a domain of the von Hippel-Lindau (VHL) tumor suppressor, thereby preventing oxygen-dependent VHL-mediated proteasomal degradation of HIF-1a [56]. On the other hand, it has been reported that HIF-1 directly binds to the promoter of NR4A1 and enhances its expression under hypoxic conditions [58].…”

Section: Nr4a1 As a Regulator Of Protein Stabilitymentioning

confidence: 99%