ORCID Profile
0000-0003-1934-0139
Current Organisation
University of North Carolina at Chapel Hill
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Publisher: Proceedings of the National Academy of Sciences
Date: 26-10-2020
Abstract: Retinal ischemia causes hypoxia-induced neovascularization that stimulates production of proangiogenic cytokines such as VEGF by the hypoxia-inducible transcription factors HIF-1 and HIF-2. Current therapies for ischemic retinal diseases target circulating VEGF but do not modulate the activity of the transcription factors that control its production. We demonstrate that inhibiting HIF-mediated transcription with a peptide derived from the intrinsically disordered protein CITED2, a negative feedback regulator of HIF-1α, reduces pathological angiogenesis in a mouse model of ischemic retinopathy. Combining the CITED2 peptide with the VEGF-Trap aflibercept causes potent suppression of neovascularization and promotes revascularization of the ischemic retina, an outcome not observed for anti-VEGF agents alone, suggesting that dual targeting of the HIF transcription factors and VEGF may be advantageous.
Publisher: Proceedings of the National Academy of Sciences
Date: 10-01-2022
Abstract: Intrinsically disordered proteins must frequently compete for binding to shared interaction hubs to perform their cellular functions. Here, we describe the mechanism by which two disordered proteins that regulate the transcriptional response to hypoxia compete for binding to the folded TAZ1 domain of the transcriptional coactivators CBP and p300. CITED2, a negative feedback regulator of HIF-1α, displaces HIF-1α from TAZ1 in a unidirectional, switch-like manner. Efficient competition for binding of the TAZ1 domain is highly dependent on the flexibility and multivalency of the HIF-1α and CITED2 activation domains. Differences in the strength of coupling of the CITED2 and HIF-1α binding motifs are key determinants of unidirectionality and underscore the role of multivalency in regulation of cellular processes by disordered proteins.
Publisher: Wiley
Date: 11-06-2015
Publisher: Elsevier BV
Date: 12-2021
Publisher: American Chemical Society (ACS)
Date: 18-02-2019
Location: United States of America
No related grants have been discovered for Rebecca Berlow.