dc.contributor.author | Foxler, DE | en_US |
dc.contributor.author | Bridge, KS | en_US |
dc.contributor.author | Foster, JG | en_US |
dc.contributor.author | Grevitt, P | en_US |
dc.contributor.author | Curry, S | en_US |
dc.contributor.author | Shah, KM | en_US |
dc.contributor.author | Davidson, KM | en_US |
dc.contributor.author | Nagano, A | en_US |
dc.contributor.author | Gadaleta, E | en_US |
dc.contributor.author | Rhys, HI | en_US |
dc.contributor.author | Kennedy, PT | en_US |
dc.contributor.author | Hermida, MA | en_US |
dc.contributor.author | Chang, T-Y | en_US |
dc.contributor.author | Shaw, PE | en_US |
dc.contributor.author | Reynolds, LE | en_US |
dc.contributor.author | McKay, TR | en_US |
dc.contributor.author | Wang, H-W | en_US |
dc.contributor.author | Ribeiro, PS | en_US |
dc.contributor.author | Plevin, MJ | en_US |
dc.contributor.author | Lagos, D | en_US |
dc.contributor.author | Lemoine, NR | en_US |
dc.contributor.author | Rajan, P | en_US |
dc.contributor.author | Graham, TA | en_US |
dc.contributor.author | Chelala, C | en_US |
dc.contributor.author | Hodivala-Dilke, KM | en_US |
dc.contributor.author | Spendlove, I | en_US |
dc.contributor.author | Sharp, TV | en_US |
dc.date.accessioned | 2018-07-13T16:49:26Z | |
dc.date.available | 2018-05-28 | en_US |
dc.date.issued | 2018-08 | en_US |
dc.date.submitted | 2018-07-05T15:07:13.366Z | |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/42128 | |
dc.description.abstract | The 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.sponsorship | RCUK | 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.language | eng | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | EMBO Mol Med | en_US |
dc.subject | HIF‐1 | en_US |
dc.subject | LIMD1 | en_US |
dc.subject | adaptive hypoxic response | en_US |
dc.subject | lung cancer | en_US |
dc.subject | tumour suppressor | en_US |
dc.title | A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia. | en_US |
dc.type | Article | |
dc.identifier.doi | 10.15252/emmm.201708304 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/29930174 | en_US |
pubs.issue | 8 | en_US |
pubs.notes | No embargo | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 10 | en_US |