title: The centrosomal protein Tax1 binding protein 2 is a novel tumor suppressor in hepatocellular carcinoma regulated by cyclin-dependent kinase 2.
abstract: Deregulation of cellular-signaling pathways by the inactivation of tumor-suppressor genes is one of the major causes of hepatocellular carcinoma (HCC). In this study, we identified Tax1 binding protein 2 (TAX1BP2) as a novel tumor-suppressor gene in HCC. TAX1BP2 transcript was frequently underexpressed (42.2% with T/NT <0.5; P < 0.03) in HCCs, and underexpression of TAX1BP2 was associated with poorer overall survival rates in patients after surgical resection. An effector domain (ED) for TAX1BP2 tumor-suppressor activity was mapped to the amino-acid residues 267-756. Transient or stable expression of either full-length or ED of TAX1BP2 significantly suppressed HCC cell tumorigenicity through the activation of the p38/p53/p21 pathway. In contrast, silencing of TAX1BP2 by short interfering RNA remarkably suppressed the activation of the p38/p53/p21 pathway. Finally, phosphorylation of TAX1BP2 at serine-763 by cyclin-dependent kinase (CDK)2 abolished the TAX1BP2-mediated p38 activation and tumor-suppressive activity, indicating that TAX1BP2 can adapt CDK2 signaling to the p38/p53/p21 pathway.
  
  
  CONCLUSIONS
  Taken together, our data provide the first evidence that TAX1BP2 is a CDK2-regulated tumor-suppressor gene in HCC and is a novel activator of the p38/p53/p21 pathway.
authors.affiliation: Department of Anatomy, The University of Hong Kong, Hong Kong, China.
authors.forename: Wai-Lung
authors.initials: WL
authors.lastname: Lai
authors.forename: Wing-Yan
authors.initials: WY
authors.lastname: Hung
authors.forename: Leo Lap-Yan
authors.initials: LL
authors.lastname: Wong
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Veronica Yee-Law
authors.initials: VY
authors.lastname: Leong
authors.forename: Joyce Man-Fong
authors.initials: JM
authors.lastname: Lee
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Jin
authors.forename: Yick-Pang
authors.initials: YP
authors.lastname: Ching
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018385:Centrosome / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; C494631:VAC14 protein, human; D051357:Cyclin-Dependent Kinase 2