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dc.contributor.authorFoxler, DEen_US
dc.contributor.authorBridge, KSen_US
dc.contributor.authorFoster, JGen_US
dc.contributor.authorGrevitt, Pen_US
dc.contributor.authorCurry, Sen_US
dc.contributor.authorShah, KMen_US
dc.contributor.authorDavidson, KMen_US
dc.contributor.authorNagano, Aen_US
dc.contributor.authorGadaleta, Een_US
dc.contributor.authorRhys, HIen_US
dc.contributor.authorKennedy, PTen_US
dc.contributor.authorHermida, MAen_US
dc.contributor.authorChang, T-Yen_US
dc.contributor.authorShaw, PEen_US
dc.contributor.authorReynolds, LEen_US
dc.contributor.authorMcKay, TRen_US
dc.contributor.authorWang, H-Wen_US
dc.contributor.authorRibeiro, PSen_US
dc.contributor.authorPlevin, MJen_US
dc.contributor.authorLagos, Den_US
dc.contributor.authorLemoine, NRen_US
dc.contributor.authorRajan, Pen_US
dc.contributor.authorGraham, TAen_US
dc.contributor.authorChelala, Cen_US
dc.contributor.authorHodivala-Dilke, KMen_US
dc.contributor.authorSpendlove, Ien_US
dc.contributor.authorSharp, TVen_US
dc.description.abstractThe adaptive cellular response to low oxygen tensions is mediated by the hypoxia-inducible factors (HIFs), a family of heterodimeric transcription factors composed of HIF-α and HIF-β subunits. Prolonged HIF expression is a key contributor to cellular transformation, tumorigenesis and metastasis. As such, HIF degradation under hypoxic conditions is an essential homeostatic and tumour-suppressive mechanism. LIMD1 complexes with PHD2 and VHL in physiological oxygen levels (normoxia) to facilitate proteasomal degradation of the HIF-α subunit. Here, we identify LIMD1 as a HIF-1 target gene, which mediates a previously uncharacterised, negative regulatory feedback mechanism for hypoxic HIF-α degradation by modulating PHD2-LIMD1-VHL complex formation. Hypoxic induction of LIMD1 expression results in increased HIF-α protein degradation, inhibiting HIF-1 target gene expression, tumour growth and vascularisation. Furthermore, we report that copy number variation at the LIMD1 locus occurs in 47.1% of lung adenocarcinoma patients, correlates with enhanced expression of a HIF target gene signature and is a negative prognostic indicator. Taken together, our data open a new field of research into the aetiology, diagnosis and prognosis of LIMD1-negative lung cancers.en_US
dc.description.sponsorshipRCUK | Biotechnology and Biological Sciences Research Council (BBSRC). BB/L027755/1BB/N018818/1. RCUK | Medical Research Council (MRC) MR/N009185/1MR/L008505/1. Cancer Research UK (CRUK) CRUK‐A12733C19198/A15339C16420/A18066C355/A25137. Barts and The London School of Medicine and Dentistry 0000 0003 1861 7984.en_US
dc.relation.ispartofEMBO Mol Meden_US
dc.subjectadaptive hypoxic responseen_US
dc.subjectlung canceren_US
dc.subjecttumour suppressoren_US
dc.titleA HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia.en_US
pubs.notesNo embargoen_US

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