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Prohibitin 1 regulates the H19-Igf2 axis and proliferation in hepatocytes
- Title
- Prohibitin 1 regulates the H19-Igf2 axis and proliferation in hepatocytes
- Authors
- Ramani K.; Mavila N.; Ko K.S.; Mato J.M.; Lu S.C.
- Ewha Authors
- 고광석
- SCOPUS Author ID
- 고광석
- Issue Date
- 2016
- Journal Title
- Journal of Biological Chemistry
- ISSN
- 0021-9258
- Citation
- Journal of Biological Chemistry vol. 291, no. 46, pp. 24148 - 24159
- Publisher
- American Society for Biochemistry and Molecular Biology Inc.
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- Prohibitin 1 (PHB1) is a mitochondrial chaperone that regulates cell growth. Phb1 knock-out mice exhibit liver injury and hepatocellular carcinoma (HCC). Phb1 knock-out livers show induction of tumor growth-associated genes, H19 and insulin-like growth factor 2 (Igf2). These genes are controlled by the imprinting control region (ICR) containing CCCTC-binding transcription factor (CTCF)-binding sites. Because Phb1 knock-out mice exhibited induction of H19 and Igf2, we hypothesized that PHB1-mediated regulation of the H19-Igf2 axis might control cell proliferation in normal hepatocytes. H19 and Igf2 were induced (8-20-fold) in 3-week-old Phb1 knock-out livers, in Phb1 siRNA-treated AML12 hepatocytes (2-fold), and HCC cell lines when compared with control. Phb1 knockdown lowered CTCF protein in AML12 by ∼30% when compared with control. CTCF overexpression lowered basal H19 and Igf2 expression by 30% and suppressed Phb1 knockdown-mediated induction of these genes. CTCF and PHB1 co-immunoprecipitated and colocalized on the ICR element, and Phb1 knockdown lowered CTCF ICR binding activity. The results suggest that PHB1 and CTCF cooperation may control the H19-Igf2 axis. Human HCC tissues with high levels of H19 and IGF2 exhibited a 40-50% reduction in PHB1 and CTCF expression and their ICR binding activity. Silencing Phb1 or overexpressing H19 in the mouse HCC cell line, SAMe-D, induced cell growth. Blocking H19 induction prevented Phb1 knockdown-mediated growth, whereas H19 overexpression had the reverse effect. Interestingly H19 silencing induced PHB1 expression. Taken together, our results demonstrate that the H19-Igf2 axis is negatively regulated by CTCF-PHB1 cooperation and that H19 is involved in modulating the growth-suppressive effect of PHB1 in the liver. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
- DOI
- 10.1074/jbc.M116.744045
- Appears in Collections:
- 신산업융합대학 > 식품영양학과 > Journal papers
- Files in This Item:
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Prohibitin 1 Regulates the H19-Igf2 Axis.pdf(2.23 MB)
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