Jungyoon Cho

Estrogen receptor beta inhibits transcriptional activity of hypoxia inducible factor-1 through the downregulation of arylhydrocarbon receptor nuclear translocator

IntroductionEstrogen receptor (ER) β is predicted to play an important role in prevention of breast cancer development and metastasis. We have shown previously that ERβ inhibits hypoxia inducible factor (HIF)-1α mediated transcription, but the mechanism by which ERβ works to exert this effect is not understood.MethodsVascular endothelial growth factor (VEGF) was measured in conditioned medium by enzyme-linked immunosorbent assays. Reverse transcription polymerase chain reaction (RT-PCR), Western blotting, immunoprecipitation, luciferase assays and chromatin immunoprecipitation (ChIP) assays were used to ascertain the implication of ERβ on HIF-1 function.ResultsIn this study, we found that the inhibition of HIF-1 activity by ERβ expression was correlated with ERβs ability to degrade aryl hydrocarbon receptor nuclear translocator (ARNT) via ubiquitination processes leading to the reduction of active HIF-1α/ARNT complexes. HIF-1 repression by ERβ was rescued by overexpression of ARNT as examined by hypoxia-responsive element (HRE)-driven luciferase assays. We show further that ERβ attenuated the hypoxic induction of VEGF mRNA by directly decreasing HIF-1α binding to the VEGF gene promoter.ConclusionsThese results show that ERβ suppresses HIF-1α-mediated transcription via ARNT down-regulation, which may account for the tumour suppressive function of ERβ.

Hypoxic activation of unoccupied estrogen-receptor-alpha is mediated by hypoxia-inducible factor-1 alpha.

The estrogen receptor (ER) plays an important role in breast cancer development and progression. Hypoxia has been shown to modulate the level of ERalpha expression, which is intimately associated with the biology of breast carcinomas. However, the effect of hypoxia on ERalpha-mediated transactivation is largely unknown. In this report, we have examined ligand-independent transcriptional activation of ERalpha by hypoxia. The hypoxia-induced ERalpha-mediated transcriptional response was inhibited by the ER antagonist ICI 182,780 as determined by transient expression of ERalpha and ER-responsive reporter plasmids in the HEK 293 cells. Hypoxic activation of ERalpha was dependent on the increased expression of hypoxia-inducible factor-1alpha (HIF-1alpha), as examined in HEK 293 cells under conditions of normoxia. These results indicate that hypoxia activates ERalpha in a ligand-independent manner, possibly through the interaction between HIF-1alpha and ERalpha.

Hypoxia-inducible factor 1α activates and is inhibited by unoccupied estrogen receptor β

Previously, we showed that hypoxia induces ligand‐independent estrogen receptor (ER)α activation. In this study, we found that hypoxia activated the ERβ‐mediated transcriptional response in HEK293 cells in the absence of estrogen. ERβ transactivation was induced by the expression of the hypoxia‐inducible factor 1α (HIF‐1α) under normoxia. ERβ interacted with HIF‐1α, and SRC1 and CBP potentiated the effect of HIF‐1α on ERβ‐mediated transcription. We then examined the effect of ERβ on HIF1‐α transactivation. Surprisingly, ERβ attenuated the transcriptional activity of HIF‐1α, as measured by HRE‐driven reporter gene expression and hypoxic induction of VEGF mRNA in HEK293 cells. Taken together, these data show that HIF‐1α activates ERβ‐mediated transcription in the absence of a ligand, and ERβ inhibits HIF‐1α‐mediated transcription.

Current Status of Gene Therapy as a New Drug Delivery System

Gene therapy is fundamentally a sophisticated drug delivery technology to cure a disease by the transfer of genetic material to modify living cells. In other words, the gene is used as a therapeutic drug much like a chemical compound is employed in chemotherapy. Currently almost 600 clinical trials are underway worldwide since the first clinical trials carried out in 1990 to treat adenosine deaminase deficiency using retroviral vectors. Despite the great progress still is there no gene therapy product being approved as a new drug. This is partly due to a lack of an ideal gene delivery system that is safe and can provide stable, optimal level production of the therapeutic proteins in the cell. This review covers the current status of several different biological and physico-chemical agents that are being developed as gene delivery vehicles. Although gene therapy promises great hopes toward the cure of a broad spectrum of genetic and acquired diseases, the success of gene therapy heavily asks for the development of vector systems for safe and efficient application in humans.