title: S-adenosylmethionine regulates dual-specificity mitogen-activated protein kinase phosphatase expression in mouse and human hepatocytes.
abstract: Increased mitogen-activated protein kinase (MAPK) activity correlates with a more malignant hepatocellular carcinoma (HCC) phenotype. There is a reciprocal regulation between p44/42 MAPK (extracellular signal-regulated kinase [ERK]1/2) and the dual-specificity MAPK phosphatase MKP-1/DUSP1. ERK phosphorylates DUSP1, facilitating its proteasomal degradation, whereas DUSP1 inhibits ERK activity. Methionine adenosyltransferase 1a (Mat1a) knockout (KO) mice express hepatic S-adenosylmethionine (SAM) deficiency and increased ERK activity and develop HCC. The aim of this study was to examine whether DUSP1 expression is regulated by SAM and if so, elucidate the molecular mechanisms. Studies were conducted using Mat1a KO mice livers, cultured mouse and human hepatocytes, and 20S and 26S proteasomes. DUSP1 messenger RNA (mRNA) and protein levels were reduced markedly in livers of Mat1a KO mice and in cultured mouse and human hepatocytes with protein falling to lower levels than mRNA. SAM treatment protected against the fall in DUSP1 mRNA and protein levels in mouse and human hepatocytes. SAM increased DUSP1 transcription, p53 binding to DUSP1 promoter, and stability of its mRNA and protein. Proteasomal chymotrypsin-like and caspase-like activities were increased in Mat1a KO livers and cultured hepatocytes, which was blocked by SAM treatment. SAM inhibited chymotrypsin-like and caspase-like activities by 40% and 70%, respectively, in 20S proteasomes and caused rapid degradation of some of the 26S proteasomal subunits, which was blocked by the proteasome inhibitor MG132. SAM treatment in Mat1a KO mice for 7 days raised SAM, DUSP1, mRNA and protein levels and lowered proteosomal and ERK activities.
  
  
  CONCLUSIONS
  DUSP1 mRNA and protein levels are lower in Mat1a KO livers and fall rapidly in cultured hepatocytes. SAM treatment increases DUSP1 expression through multiple mechanisms, and this may suppress ERK activity and malignant degeneration.
authors.affiliation: Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, The Southern California Research Center for Alcoholic and Pancreatic Diseases & Cirrhosis, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Maria Lauda
authors.initials: ML
authors.lastname: Tomasi
authors.forename: Komal
authors.initials: K
authors.lastname: Ramani
authors.forename: Fernando
authors.initials: F
authors.lastname: Lopitz-Otsoa
authors.forename: Manuel S
authors.initials: MS
authors.lastname: Rodríguez
authors.forename: Tony W H
authors.initials: TW
authors.lastname: Li
authors.forename: Kwangsuk
authors.initials: K
authors.lastname: Ko
authors.forename: Heping
authors.initials: H
authors.lastname: Yang
authors.forename: Fawzia
authors.initials: F
authors.lastname: Bardag-Gorce
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Iglesias-Ara
authors.forename: Francesco
authors.initials: F
authors.lastname: Feo
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Pascale
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
mesh_terms: D000818:Animals; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D008297:Male; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism*
chemical_list: D012436:S-Adenosylmethionine; C490703:Mat1a protein, mouse; D008716:Methionine Adenosyltransferase; D048049:Extracellular Signal-Regulated MAP Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease