Comprehensive analysis of the Hif1α interactome and its regulation by post-translational modifications

SCHEME: CORE

CALL: 2017

DOMAIN: BM - Translational Biomedical Research

FIRST NAME: Gunnar

LAST NAME: Dittmar

INDUSTRY PARTNERSHIP / PPP: No

INDUSTRY / PPP PARTNER:

HOST INSTITUTION: LIH

KEYWORDS: Hif-1, HIF1a, interactome, PTM, hypoxia, regulatory switch, PrISMa, SILAC

START: 2018-02-01

END:

WEBSITE: https://www.lih.lu

Submitted Abstract

All human cells need oxygen for energy production by oxidative phosphorylation. If the oxygen levels are low, cells switch from oxidative phosphorylation to glycolysis. The Hif1a subunit of the transcription factor HIF-1 is essential for this regulatory switch. The switch is regulated by the oxygen level dependent formation of hydroxyproline on the Hif1a subunit which in turn is recognized by the VHL-E3 ligase leading to Hif1a’s degradation by the ubiquitin-proteasome system. In addition to these modifications, large scale studies of post-translationally modified (PTM) proteins identified 60 other PTMs on Hif1a. The regulatory function of these modifications is largely unknown. In this study, we are setting out to define a comprehensive interactome of Hif1a and its regulation by PTMs. Therefore, we are using a newly developed screening technology, protein interaction screening on peptide matrices (PrISMa). This technology allows the simultaneous identification of the interactome and its regulation by PTMs for a protein like Hif1a. This technology will be extended to a multiplexed version by combining it with metabolic isotope labelling (SILAC). The study will lead to a better understanding of the regulation by Hif1a and will identify new regulatory pathways, which can be exploited for targeted cancer therapies.

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