title: Prosurvival function of the cellular apoptosis susceptibility/importin-α1 transport cycle is repressed by p53 in liver cancer.
abstract: Proteins of the karyopherin superfamily including importins and exportins represent an essential part of the nucleocytoplasmic transport machinery. However, the functional relevance and regulation of karyopherins in hepatocellular carcinoma (HCC) is poorly understood. Here we identified cellular apoptosis susceptibility (CAS, exportin-2) and its transport substrate importin-α1 (imp-α1) among significantly up-regulated transport factor genes in HCC. Disruption of the CAS/imp-α1 transport cycle by RNAi in HCC cell lines resulted in decreased tumor cell growth and increased apoptosis. The apoptotic phenotype upon CAS depletion could be recapitulated by direct knockdown of the X-linked inhibitor of apoptosis (XIAP) and partially reverted by XIAP overexpression. In addition, XIAP and CAS mRNA expression levels were correlated in HCC patient samples (r=0.463; P<0.01), supporting the in vivo relevance of our findings. Furthermore, quantitative mass spectrometry analyses of murine HCC samples (p53-/- versus p53+/+) indicated higher protein expression of CAS and imp-α1 in p53-/- tumors. Consistent with a role of p53 in regulating the CAS/imp-α1 transport cycle, we observed that both transport factors were repressed upon p53 induction in a p21-dependent manner.
  
  
  CONCLUSIONS
  The CAS/imp-α1 transport cycle is linked to XIAP and is required to maintain tumor cell survival in HCC. Moreover, CAS and imp-α1 are targets of p53-mediated repression, which represents a novel aspect of p53's ability to control tumor cell growth in hepatocarcinogenesis.
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkler
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ori
authors.forename: Kerstin
authors.initials: K
authors.lastname: Holzer
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauch
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Eiteneuer
authors.forename: Federico
authors.initials: F
authors.lastname: Pinna
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.forename: Amparo
authors.initials: A
authors.lastname: Andres-Pons
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Justo Lorenzo
authors.initials: JL
authors.lastname: Bermejo
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Martin
authors.initials: M
authors.lastname: Beck
authors.forename: Stephan
authors.initials: S
authors.lastname: Singer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D029563:Cellular Apoptosis Susceptibility Protein / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010641:Phenotype; D016159:Tumor Suppressor Protein p53 / Q000502:physiology* / Q000633:toxicity; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D028901:alpha Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D029563:Cellular Apoptosis Susceptibility Protein; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D028901:alpha Karyopherins; C087978:karyopherin alpha 2