The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress.
Activation of the p53 network plays a central role in the inflammatory stress response associated with ulcerative colitis and may modulate cancer risk in patients afflicted with this chronic disease. Here, we describe the gene expression profiles associated with four microenvironmental components of the inflammatory response (NO*, H2O2, DNA replication arrest, and hypoxia) that result in p53 stabilization and activation. Isogenic HCT116 and HCT116 TP53-/- colon cancer cells were exposed to the NO* donor Sper/NO, H2O2, hypoxia, or hydroxyurea, and their mRNA was analyzed using oligonucleotide microarrays. Overall, 1,396 genes changed in a p53-dependent manner (P < 0.001), with the majority representing a "unique" profile for each condition. Only 14 genes were common to all four conditions. Included were eight known p53 target genes. Hierarchical sample clustering distinguished early (1 and 4 hours) from late responses (8, 12, and 24 hours), and each treatment was differentiated from the others. Overall, NO* and hypoxia stimulated similar transcriptional responses. Gene ontology analysis revealed cell cycle as a key feature of stress responses and confirmed the similarity between NO* and hypoxia. Cell cycle profiles analyzed by flow cytometry showed that NO* and hypoxia induced quiescent S-phase and G2-M arrest. Using a novel bioinformatic algorithm, we identified several putative p53-responsive elements among the genes induced in a p53-dependent manner, including four [KIAA0247, FLJ12484, p53CSV (HSPC132), and CNK (PLK3)] common to all exposures. In summary, the inflammatory stress response is a complex, integrated biological network in which p53 is a key molecular node regulating gene expression.
Staib
Frank
F
Laboratories of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.
Robles
Ana I
AI
Varticovski
Lyuba
L
Wang
Xin W
XW
Zeeberg
Barry R
BR
Sirotin
Michail
M
Zhurkin
Victor B
VB
Hofseth
Lorne J
LJ
Hussain
S Perwez
SP
Weinstein
John N
JN
Galle
Peter R
PR
Harris
Curtis C
CC
D002453:Cell Cycle; D015687:Cell Hypoxia; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D045325:HCT116 Cells; D006801:Humans; D006861:Hydrogen Peroxide; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013096:Spermine / Q000031:analogs & derivatives; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C091861:spermine nitric oxide complex; D013096:Spermine; D006861:Hydrogen Peroxide