Mudie, S., Bandarra, D., Batie, M., Biddlestone, J., Moniz, S., Ortmann, B., Shmakova, A. and Rocha, S. (2014) PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia. Cell Cycle, 13(24), pp. 3878-3891. (doi: 10.4161/15384101.2014.972889) (PMID:25558831) (PMCID:PMC4614811)
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Abstract
Hypoxia is an important developmental cue for multicellular organisms but it is also a contributing factor for several human pathologies, such as stroke, cardiovascular diseases and cancer. In cells, hypoxia activates a major transcriptional program coordinated by the Hypoxia Inducible Factor (HIF) family. HIF can activate more than one hundred targets but not all of them are activated at the same time, and there is considerable cell type variability. In this report we identified the paired-like homeodomain pituitary transcription factor (PITX1), as a transcription factor that helps promote specificity in HIF-1α dependent target gene activation. Mechanistically, PITX1 associates with HIF-1β and it is important for the induction of certain HIF-1 dependent genes but not all. In particular, PITX1 controls the HIF-1α-dependent expression of the histone demethylases; JMJD2B, JMJD2A, JMJD2C and JMJD1B. Functionally, PITX1 is required for the survival and proliferation responses in hypoxia, as PITX1 depleted cells have higher levels of apoptotic markers and reduced proliferation. Overall, our study identified PITX1 as a key specificity factor in HIF-1α dependent responses, suggesting PITX1 as a protein to target in hypoxic cancers.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Biddlestone, Dr John |
| Authors: | Mudie, S., Bandarra, D., Batie, M., Biddlestone, J., Moniz, S., Ortmann, B., Shmakova, A., and Rocha, S. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing |
| Journal Name: | Cell Cycle |
| Publisher: | Taylor and Francis (Routledge) |
| ISSN: | 1538-4101 |
| ISSN (Online): | 1551-4005 |
| Published Online: | 03 January 2015 |
| Copyright Holders: | Copyright © 2014 The Authors |
| First Published: | First published in Cell Cycle 13(24):3878-3891 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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