TY - JOUR
T1 - Identification of cell cycle regulatory genes as principal targets of p53-mediated transcriptional repression
AU - Spurgers, Kevin B.
AU - Gold, David L.
AU - Coombes, Kevin R.
AU - Bohnenstiehl, Nicole L.
AU - Mullins, Brian
AU - Meyn, Raymond E.
AU - Logothetis, Christopher J.
AU - McDonnell, Timothy J.
PY - 2006/9/1
Y1 - 2006/9/1
N2 - 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 ≤ 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 ≤ 5 × 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.
AB - 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 ≤ 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 ≤ 5 × 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.
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U2 - 10.1074/jbc.M513901200
DO - 10.1074/jbc.M513901200
M3 - Article
C2 - 16798743
AN - SCOPUS:33748752327
SN - 0021-9258
VL - 281
SP - 25134
EP - 25142
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 35
ER -