title: RB and p53 cooperate to prevent liver tumorigenesis in response to tissue damage.
abstract: OBJECTIVE
  The tumor suppressors retinoblastoma (RB) and p53 are important regulators of the cell cycle. Although human cancer cells inactivate RB and p53 by many mechanisms, the cooperative roles of these proteins in tumorigenesis are complex and tissue specific. We analyzed the cooperation of RB and p53 in liver development and pathogenesis of hepatocellular carcinoma.
  
  
  METHODS
  Spontaneous and carcinogen-induced (diethylnitrosamine) tumorigenesis were studied in mice with liver-specific deletions of Rb and/or p53 (Rbf/f;albcre+, p53f/f;albcre+ and Rbf/f; p53f/f;albcre+ mice). Genotype, histologic, immunohistochemical, microarray, quantitative polymerase chain reaction, immunoblot, and comparative genomic hybridization analyses were performed using normal and tumor samples. Comparative microarray analyses were performed against publicly available human microarray data sets.
  
  
  RESULTS
  Deletion of RB and p53 from livers of mice deregulated the transcriptional programs associated with human disease. These changes were not sufficient for spontaneous tumorigenesis; potent quiescence mechanisms compensated for loss of these tumor suppressors. In response to hepatocarcinogen-induced damage, distinct and cooperative roles of RB and p53 were revealed; their loss affected cell cycle control, checkpoint response, and genome stability. In damaged tissue, combined loss of RB and p53 resulted in early lesion formation, aggressive tumor progression, and gene expression signatures and histologic characteristics of advanced human hepatocellular carcinoma.
  
  
  CONCLUSIONS
  The effects RB and p53 loss are determined by the tissue environment; cell stresses that promote aggressive disease reveal the functions of these tumor suppressors.
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: A Kathleen
authors.initials: AK
authors.lastname: McClendon
authors.forename: Jeffry L
authors.initials: JL
authors.lastname: Dean
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Fu
authors.forename: Dayana B
authors.initials: DB
authors.lastname: Rivadeneira
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reed
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Bourgo
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Witkiewicz
authors.forename: Sankar
authors.initials: S
authors.lastname: Addya
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Mayhew
authors.forename: H Leighton
authors.initials: HL
authors.lastname: Grimes
authors.forename: Paolo
authors.initials: P
authors.lastname: Fortina
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002453:Cell Cycle; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D004052:Diethylnitrosamine; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D004052:Diethylnitrosamine