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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
고광석scopus
Issue Date
2016
Journal Title
Journal of Biological Chemistry
ISSN
0021-9258JCR Link
Citation
vol. 291, no. 46, pp. 24148 - 24159
Publisher
American Society for Biochemistry and Molecular Biology Inc.
Indexed
SCI; SCIE; SCOPUS WOS scopus
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
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신산업융합대학 > 식품영양학과 > Journal papers
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