Basic‐helix‐loop‐helix (bHLH) transcription factor DEC2 negatively regulates vascular endothelial growth factor expression

Feb 1, 2008Genes to cells : devoted to molecular & cellular mechanisms

The DEC2 protein reduces the production of a key blood vessel growth factor

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Abstract

DEC2, a transcription factor, negatively regulates vascular endothelial growth factor (VEGF) expression under hypoxic conditions.

DEC2, but not DEC1, was found to suppress VEGF gene expression when oxygen levels are low.
The interaction of DEC2 with hypoxia-inducible factor 1alpha (HIF-1alpha) was confirmed, while no interaction with arylhydrocarbon receptor nuclear translocator 1 (ARNT1) was observed.
Over-expression of DEC2 reduced HIF-1alpha's binding to the hypoxia response element in the VEGF promoter.
Knockdown of DEC2 led to increased binding of HIF-1alpha to the VEGF promoter.
Circadian patterns showed that DEC2 expression fluctuated in opposition to VEGF levels in cartilage.

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DEC1 (BHLHB2/Sharp2/Stra13) and DEC2 (BHLHB3/Sharp1) are basic-helix-loop-helix (bHLH) transcription factors, involved in cellular differentiation, responses to hypoxia and circadian rhythms. We recently showed that the expression of DEC1 and DEC2 was up-regulated by hypoxia; however, the functions of these two factors under hypoxic conditions have not been elucidated in detail. It is well established that the expression of vascular endothelial growth factor (VEGF) is up-regulated by hypoxia, and the expression of VEGF in response to hypoxia depends on transcriptional activation by a heterodimer comprising hypoxia-inducible factor 1alpha (HIF-1alpha) and arylhydrocarbon receptor nuclear translocator 1 (ARNT1). In the present study, we showed that DEC2, but not DEC1, suppressed VEGF gene expression under hypoxic conditions. DEC2 protein was co-immunoprecipitated with HIF-1alpha but not with ARNT1. The binding of HIF-1alpha to the hypoxia response element (HRE) in the VEGF promoter was decreased by DEC2 over-expression, and increased by DEC2 knockdown. We also showed that the circadian expression of VEGF showed a reciprocal pattern to that of DEC2 in cartilage. DEC2 had a circadian oscillation in implanted Sarcoma 180 cells. We conclude that DEC2 negatively regulates VEGF expression and plays an important role in the pathological conditions in which VEGF is involved.

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Basic‐helix‐loop‐helix (bHLH) transcription factor DEC2 negatively regulates vascular endothelial growth factor expression

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