By the same authors

A HIF-LIMD1 negative feedback mechanism drives the adaptive response to hypoxia and mitigates pro-tumorigenic hypoxic effects

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  • Daniel E Foxler
  • John G Foster
  • Paul Grevitt
  • Sean Curry
  • Kunal M Shah
  • Kathryn M Davidson
  • Ai Nagano
  • Emanuela Gadaleta
  • Hefin I. Rhys
  • Paul T Kennedy
  • Miguel A Hermida
  • Ting-Yu Chang
  • Peter E Shaw
  • Louise E Reynolds
  • Tristan R. McKay
  • Hsei-Wei Wang
  • Paulo S Ribeiro
  • Nicholas R. Lemoine
  • Prabhakar Rajan
  • Trevor A Graham
  • Claude Chelala
  • Kairbaan M Hodivala-Dilke
  • Ian Spendlove
  • Tyson V Sharp


Publication details

JournalEMBO Molecular Medicine
DateAccepted/In press - 14 May 2018
DateE-pub ahead of print - 21 Jun 2018
DatePublished (current) - 1 Jul 2018
Issue number7
Number of pages18
Early online date21/06/18
Original languageEnglish


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.

Bibliographical note

© 2018, The Author(s).

    Research areas

  • Adenocarcinoma/diagnosis, Adult, Aged, Aged, 80 and over, Animals, Carcinogenesis/genetics, Cell Hypoxia/genetics, Cell Line, Tumor, Feedback, Physiological, Female, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit/genetics, Intracellular Signaling Peptides and Proteins/genetics, LIM Domain Proteins/genetics, Lung Neoplasms/diagnosis, Male, Mice, Middle Aged, Prognosis, Survival Analysis, Vascular Endothelial Growth Factor A/genetics

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