title: ERK-dependent downregulation of Skp2 reduces Myc activity with HGF, leading to inhibition of cell proliferation through a decrease in Id1 expression.
abstract: Hepatocyte growth factor (HGF) has an inhibitory effect on human HepG2 hepatoma cell proliferation. Previously, it was shown that HGF treatment downregulated Id1 and upregulated p16(INK4a) in an ERK-dependent manner, leading to the inhibition of cellular proliferation. Here, new insight suggests that Skp2, an SCF complex component and potential prognosticator in cancer, is downregulated by injection of HGF into established HepG2 xenograft tumors. The downregulation was evident at both the mRNA and protein level and in an ERK-dependent manner. Critically, high expression of Skp2 restored HGF-inhibited cell proliferation, indicating that the inhibitory effect of HGF required the downregulation of Skp2. However, downregulation was not involved in the HGF-induced upregulation of a CDK inhibitor, p27(Kip1), a known SCF-Skp2 target. Instead, data revealed that Skp2 regulated Myc activity, which has oncogenic potential in the generation of hepatocellular carcinoma. Elevated expression of Skp2 or a mutant that is unable to associate with the SCF complex was capable of activating Myc, suggesting that Skp2 does not act on Myc as a component of the SCF complex, and thus functions as an activator of Myc independent of its role in ubiquitination. Furthermore, Skp2 regulated Id1 expression by regulating Myc activity, and the regulation of Skp2 is involved in the activity of p16 promoter through regulation of Id1 expression. Overall, these mechanistic findings provide the first evidence that ERK-dependent downregulation of Skp2 reduced Myc activity, leading to HGF-induced inhibition of cell proliferation through decreased Id1 expression.
  
  
  CONCLUSIONS
  This study elucidates the molecular details of HGF-induced inhibition of cellular proliferation in liver cancer cells.
authors.affiliation: Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama, 226-8501, Japan. ttanaka@bio.titech.ac.jp.
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Bian
authors.forename: Yuri
authors.initials: Y
authors.lastname: Takizawa
authors.forename: Tomio
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ikoma
authors.forename: Junzo
authors.initials: J
authors.lastname: Tanaka
authors.forename: Naomi
authors.initials: N
authors.lastname: Kitamura
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inagaki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komada
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D051379:Mice; D016513:Mice, SCID; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051798:Inhibitor of Differentiation Protein 1; D016271:Proto-Oncogene Proteins c-myc; D044786:S-Phase Kinase-Associated Proteins; D017228:Hepatocyte Growth Factor