title: Identification of cell cycle regulatory genes as principal targets of p53-mediated transcriptional repression.
abstract: Historically, most studies attribute p53 function to the transactivation of target genes. That p53 can selectively repress genes to affect a cellular response is less widely appreciated. Available evidence suggests that repression is important for p53-induced apoptosis and cell cycle arrest. To better establish the scope of p53-repressed target genes and the cellular processes they may affect, a global expression profiling strategy was used to identify p53-responsive genes following adenoviral p53 gene transfer (Ad-p53) in PC3 prostate cancer cells. A total of 111 genes, 0.77% of the 14,500 genes represented on the Affymetrix U133A microarray, were repressed more than 2-fold (p < or = 0.05). Validation of the array data, using reverse transcription-PCR of 20 randomly selected genes, yielded a confirmation rate of >95.5% for the complete data set. Functional over-representation analysis revealed that cell cycle regulatory genes exhibited a highly significant enrichment (p < or = 5 x 10(-28)) within the transrepressed targets. 41% of the repressed targets are cell cycle regulators. A subset of these genes exhibited repression following DNA damage, preceding cell cycle arrest, in LNCaP cells. The use of a p53 small interfering RNA strategy in LNCaP cells and the use of p53-null cell lines demonstrated that this repression is p53-dependent. These findings identify a set of genes not known previously to be down-regulated by p53 and indicate that p53-induced cell cycle arrest is a function of not only the transactivation of cell cycle inhibitors (e.g. p21) but also the repression of targets that regulate proliferation at several distinct phases of the cell cycle.
authors.affiliation: Department of Molecular Pathology, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Spurgers
authors.forename: David L
authors.initials: DL
authors.lastname: Gold
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Bohnenstiehl
authors.forename: Brian
authors.initials: B
authors.lastname: Mullins
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Meyn
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McDonnell
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53