Direct regulation of HO-1 by HIF-1α in NBS1 overexpressing cells

Autor: Chia-Yu Wu, 吳家瑜
Rok vydání: 2006
Druh dokumentu: 學位論文 ; thesis
Popis: 94
Heme oxygenase-1 (HO-1) is a rate-limiting enzyme that catalyzes oxidative degradation of heme to form biliverdin, carbon monoxide, and free iron. HO-1 confers a protective capacity to cells against oxidative injury, inflammation and apoptosis. In addition, HO-1 is believed to involve in carcinogenesis by reducing the levels of reactive oxygen species and promoting proliferation of cancer cells. Hypoxic inducible factor-1�� (HIF-1��) has been shown to regulate HO-1 expression, and the HIF-1�� binding site (HBS) has been identified in the promoter of mouse HO-1. We previously demonstrated that overexpression of a DNA double-strand break repair protein NBS1 contributes to transformation thorough the activation of phosphatidylinositol 3-kinase (PI 3-K)/Akt pathway. Preliminary results showed that NBS1 activated PI 3-K/Akt through direct interaction with the P110α subunit of PI 3-K. Akt has been shown to activate HIF-1��. Due to the activation of PI 3-K/Akt by NBS1 and Akt activates HIF-1��, I therefore speculated the mechanistic linkage of NBS1 overexpression and activation of HIF-1��/HO-1 in human cancer cells. Increased mRNA and protein expression levels of HIF-1��/HO-1 were observed in human cancer cells overexpressing NBS1 (FADU-NBS). Overexpression of HO-1 increased the transformation ability of a Rat cells (Rat-HO-1) in soft agar clonogenecity assay. Direct binding of HIF-1�� protein to the proximal promoter of HO-1 was identified in human cells by transient transfection, gel shift and chromatin immunoprecipitation assays. All these results indicated that HIF-1�� mediated HO-1 activation was indeed occurred in human cancer cells with NBS1 overexpression. This molecular event contributes to transformation and may participate in the carcinogenesis of human cancers.
Databáze: Networked Digital Library of Theses & Dissertations
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