2000 Fiscal Year Final Research Report Summary
Analysis of Transcription Machinery of Erythropoietin Gene Expression
| Project/Area Number |
11670985
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Tokyo Medical and Dental University Medical Research Institute |
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Principal Investigator |
TSUCHIYA Terumasa Tokyo Medical and Dental University Medical Research Institute , Assistant Professor, 難治疾患研究所, 助手 (20242109)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Oxygen Sensor / Hypoxic Response / Erythropoietin / Transcription Factor |
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| Research Abstract |
Erythropoietin (Epo) is the hormone that regulates red blood cell production. Expression of the Epo gene is induced in response to hypoxia. Here we report that erythropoietin leader peptide (ELP) functions as a hypoxia-inducible transcriptional cofactor. The Epo gene transcript encodes the precursor protein, pre-Epo (PreEpo), which on proteolysis produces ELP and Epo. To investigate whether hypoxic induction of Epo is regulated via a positive or negative feedback mechanism, the effect of PreEpo on the Epo gene was assayed. Transactivation of the Epo gene was observed by expression of exogenous PreEpo in a dosedependent manner. It is known that Epo gene expression is regulated by hypoxia-inducible factor 1 (HIF-1) and hepatocyte nuclear factor 4 (HNF-4). Therefore, we investigated interactions between either ELP or Epo and HIF-1 heterodimer or HNF-4 homodimer. ELP interacts with HIF-1β subunit (aryl hydrocarbon receptor nuclear translocator, ARNT). ELP is highly conserved among the species and has a tandem repeat of two consensus LXXLL motifs of co-activators for interactions with transcription factors. Site-directed mutagenesis indicated that both LXXLL motifs are essential for interaction with ARNT.
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