title: Disruption of Trp53 in livers of mice induces formation of carcinomas with bilineal differentiation.
abstract: OBJECTIVE
  p53 limits the self-renewal of stem cells from various tissues. Loss of p53, in combination with other oncogenic events, results in aberrant self-renewal and transformation of progenitor cells. It is not known whether loss of p53 is sufficient to induce tumor formation in liver.
  
  
  METHODS
  We used AlfpCre mice to create mice with liver-specific disruption of Trp53 (AlfpCre(+)Trp53(Δ2-10/Δ2-10) mice). We analyzed colony formation and genomic features and gene expression patterns in liver cells during hepatocarcinogenesis in mice with homozygous, heterozygous, and no disruption of Trp53.
  
  
  RESULTS
  Liver-specific disruption of Trp53 consistently induced formation of liver carcinomas that had bilineal differentiation. In nontransformed liver cells and cultured primary liver cells, loss of p53 (but not p21) resulted in chromosomal imbalances and increased clonogenic capacity of liver progenitor cells (LPCs) and hepatocytes. Primary cultures of hepatocytes and LPCs from AlfpCre(+)Trp53(Δ2-10/Δ2-10) mice, but not Cdkn1a(-/-) mice, formed tumors with bilineal differentiation when transplanted into immunocompromised mice. Spontaneous liver tumors that developed in AlfpCre(+)Trp53(Δ2-10/Δ2-10) mice had significant but complex alterations in expression of Rb checkpoint genes compared with chemically induced liver tumors that developed mice with wild-type Trp53.
  
  
  CONCLUSIONS
  Deletion of p53 from livers of mice is sufficient to induce tumor formation. The tumors have bilineal differentiation and dysregulation of Rb checkpoint genes.
authors.affiliation: Institute of Molecular Medicine and Max Planck Research Group on Stem Cell Aging, University of Ulm, Ulm, Germany.
authors.forename: Sarah-Fee
authors.initials: SF
authors.lastname: Katz
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.forename: Anna C
authors.initials: AC
authors.lastname: Obenauf
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Begus-Nahrmann
authors.forename: Johann M
authors.initials: JM
authors.lastname: Kraus
authors.forename: Eva M
authors.initials: EM
authors.lastname: Hoffmann
authors.forename: Johanna
authors.initials: J
authors.lastname: Duda
authors.forename: Parisa
authors.initials: P
authors.lastname: Eshraghi
authors.forename: Daniel
authors.initials: D
authors.lastname: Hartmann
authors.forename: Birgit
authors.initials: B
authors.lastname: Liss
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
authors.forename: K Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000375:Aging; D000818:Animals; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D043171:Chromosomal Instability; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D016161:Genes, Retinoblastoma; D008099:Liver / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53