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PITX1, a specificity determinant in the HIF-1?-mediated transcriptional response to hypoxia.

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-1? dependent target gene activation. Mechanistically, PITX1 associates with HIF-1? and it is important for the induction of certain HIF-1 dependent genes but not all. In particular, PITX1 controls the HIF-1?-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-1? dependent responses, suggesting PITX1 as a protein to target in hypoxic cancers.

SUBMITTER: Mudie S

PROVIDER: S-EPMC4614811 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia.

Mudie Sharon S Bandarra Daniel D Batie Michael M Biddlestone John J Moniz Sonia S Ortmann Brian B Shmakova Alena A Rocha Sonia S

Cell cycle (Georgetown, Tex.) 20140101 24

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 ...[more]

PMID: 25558831

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Project description:BACKGROUND:Hypoxia inducible factor-1 (HIF-1) is considered as the most activated transcriptional factor in response to low oxygen level or hypoxia. HIF-1 binds the hypoxia response element (HRE) sequence in the promoter of different genes, mainly through the bHLH domain and activates the transcription of genes, especially those involved in angiogenesis and EMT. Considering the critical role of bHLH in binding HIF-1 to the HRE sequence, we hypothesized that bHLH could be a promising candidate to be targeted in hypoxia condition. METHODS:We inserted an inhibitory bHLH (ibHLH) domain in a pIRES2-EGFP vector and transfected HEK293T cells with either the control vector or the designed construct. The ibHLH domain consisted of bHLH domains of both HIF-1a and Arnt, capable of competing with HIF-1 in binding to HRE sequences. The transfected cells were then treated with 200 µM of cobalt chloride (CoCl2) for 48 h to induce hypoxia. Real-time PCR and western blot were performed to evaluate the effect of ibHLH on the genes and proteins involved in angiogenesis and EMT. RESULTS:Hypoxia was successfully induced in the HEK293T cell line as the gene expression of VEGF, vimentin, and ?-catenin were significantly increased after treatment of untransfected HEK293T cells with 200 µM CoCl2. The gene expression of VEGF, vimentin, and ?-catenin and protein level of ?-catenin were significantly decreased in the cells transfected with either control or ibHLH vectors in hypoxia. However, ibHLH failed to be effective on these genes and the protein level of ?-catenin, when compared to the control vector. We also observed that overexpression of ibHLH had more inhibitory effect on gene and protein expression of N-cadherin compared to the control vector. However, it was not statistically significant. CONCLUSION:bHLH has been reported to be an important domain involved in the DNA binding activity of HIF. However, we found that targeting this domain is not sufficient to inhibit the endogenous HIF-1 transcriptional activity. Further studies about the function of critical domains of HIF-1 are necessary for developing a specific HIF-1 inhibitor.

Dataset Information

PITX1, a specificity determinant in the HIF-1?-mediated transcriptional response to hypoxia.

Publications

PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia.

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