A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia
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 β subunits. Prolonged HIF expression is a key contributor to cellular transformation, tumourigenesis and metastasis. As s...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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Wiley Open Access
2018
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| Online Access: | https://eprints.nottingham.ac.uk/53241/ |
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| author | Foxler, Daniel E. Bridge, Katherine S. Foster, John G. Grevitt, Paul Curry, Sean Shah, Kunal M. Davidson, Kathryn M. Nagano, Ai Gadaleta, Emanuela Rhys, Hefin I. Kennedy, Paul T. Hermida, Miguel A. Chang, Ting-Yu Shaw, Peter E. Reynolds, Louise E. McKay, Tristan R. Wang, Hsei- Wei Ribeiro, Paulo S. Plevin, Michael J. Lagos, Dimitris Lemoine, Nicholas R. Rajan, Prabhakar Graham, Trevor A. Chelala, Claude Hodivala-Dilke, Kairbaan M. Spendlove, Ian Sharp, Tyson V. |
| author_facet | Foxler, Daniel E. Bridge, Katherine S. Foster, John G. Grevitt, Paul Curry, Sean Shah, Kunal M. Davidson, Kathryn M. Nagano, Ai Gadaleta, Emanuela Rhys, Hefin I. Kennedy, Paul T. Hermida, Miguel A. Chang, Ting-Yu Shaw, Peter E. Reynolds, Louise E. McKay, Tristan R. Wang, Hsei- Wei Ribeiro, Paulo S. Plevin, Michael J. Lagos, Dimitris Lemoine, Nicholas R. Rajan, Prabhakar Graham, Trevor A. Chelala, Claude Hodivala-Dilke, Kairbaan M. Spendlove, Ian Sharp, Tyson V. |
| author_sort | Foxler, Daniel E. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| 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 β subunits. Prolonged HIF expression is a key contributor to cellular transformation, tumourigenesis 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. |
| first_indexed | 2025-11-14T20:27:15Z |
| format | Article |
| id | nottingham-53241 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:27:15Z |
| publishDate | 2018 |
| publisher | Wiley Open Access |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-532412020-05-04T19:41:41Z https://eprints.nottingham.ac.uk/53241/ A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia Foxler, Daniel E. Bridge, Katherine S. Foster, John G. Grevitt, Paul Curry, Sean Shah, Kunal M. Davidson, Kathryn M. Nagano, Ai Gadaleta, Emanuela Rhys, Hefin I. Kennedy, Paul T. Hermida, Miguel A. Chang, Ting-Yu Shaw, Peter E. Reynolds, Louise E. McKay, Tristan R. Wang, Hsei- Wei Ribeiro, Paulo S. Plevin, Michael J. Lagos, Dimitris Lemoine, Nicholas R. Rajan, Prabhakar Graham, Trevor A. Chelala, Claude Hodivala-Dilke, Kairbaan M. Spendlove, Ian Sharp, Tyson V. 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 β subunits. Prolonged HIF expression is a key contributor to cellular transformation, tumourigenesis 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. Wiley Open Access 2018-06-21 Article PeerReviewed Foxler, Daniel E., Bridge, Katherine S., Foster, John G., Grevitt, Paul, Curry, Sean, Shah, Kunal M., Davidson, Kathryn M., Nagano, Ai, Gadaleta, Emanuela, Rhys, Hefin I., Kennedy, Paul T., Hermida, Miguel A., Chang, Ting-Yu, Shaw, Peter E., Reynolds, Louise E., McKay, Tristan R., Wang, Hsei- Wei, Ribeiro, Paulo S., Plevin, Michael J., Lagos, Dimitris, Lemoine, Nicholas R., Rajan, Prabhakar, Graham, Trevor A., Chelala, Claude, Hodivala-Dilke, Kairbaan M., Spendlove, Ian and Sharp, Tyson V. (2018) A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia. EMBO Molecular Medicine . e8304/1-e8304/18. ISSN 1757-4684 Adaptive hypoxic response; HIF-1; LIMD1; lung cancer; Tumour suppressor http://embomolmed.embopress.org/content/early/2018/06/21/emmm.201708304 doi:10.15252/emmm.201708304 doi:10.15252/emmm.201708304 |
| spellingShingle | Adaptive hypoxic response; HIF-1; LIMD1; lung cancer; Tumour suppressor Foxler, Daniel E. Bridge, Katherine S. Foster, John G. Grevitt, Paul Curry, Sean Shah, Kunal M. Davidson, Kathryn M. Nagano, Ai Gadaleta, Emanuela Rhys, Hefin I. Kennedy, Paul T. Hermida, Miguel A. Chang, Ting-Yu Shaw, Peter E. Reynolds, Louise E. McKay, Tristan R. Wang, Hsei- Wei Ribeiro, Paulo S. Plevin, Michael J. Lagos, Dimitris Lemoine, Nicholas R. Rajan, Prabhakar Graham, Trevor A. Chelala, Claude Hodivala-Dilke, Kairbaan M. Spendlove, Ian Sharp, Tyson V. A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia |
| title | A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia |
| title_full | A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia |
| title_fullStr | A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia |
| title_full_unstemmed | A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia |
| title_short | A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia |
| title_sort | hif-limd1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia |
| topic | Adaptive hypoxic response; HIF-1; LIMD1; lung cancer; Tumour suppressor |
| url | https://eprints.nottingham.ac.uk/53241/ https://eprints.nottingham.ac.uk/53241/ https://eprints.nottingham.ac.uk/53241/ |