| Title: |
A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia |
| Authors: |
Foxler, DE; Bridge, KS; Foster, JG; Grevitt, P; Curry, S; Shah, KM; Davidson, KM; Nagano, A; Gadaleta, E; Rhys, HI; Kennedy, PT; Hermida, MA; Chang, T-Y; Shaw, PE; Reynolds, LE; McKay, T; Wang, H-W; Ribeiro, PS; Plevin, MJ; Lagos, D; Lemoine, NR; Rajan, P; Graham, TA; Chelala, C; Hodivala-Dilke, KM; Spendlove, I; Sharp, TV |
| Publisher Information: |
EMBO Press |
| Publication Year: |
2018 |
| Collection: |
eSpace - Manchester Metropolitan University's Research Repository |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://e-space.mmu.ac.uk/621352/; http://embomolmed.embopress.org/content/10/8/e8304 |
| Availability: |
https://e-space.mmu.ac.uk/621352/7/A%20HIF%20LIMD1%20negative%20feedback.pdf |
| Rights: |
cc_by_4 ; info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.B5CA784 |
| Database: |
BASE |