Identification and classification of p53-regulated genes.

Sequence-specific transactivation by p53 is essential to its role as a tumor suppressor. A modified tetracycline-inducible system was established to search for transcripts that were activated soon after p53 induction. Among 9,954 unique transcripts identified by serial analysis of gene expression, 34 were increased more than 10-fold; 31 of these had not previously been known to be regulated by p53. The transcription patterns of these genes, as well as previously described p53-regulated genes, were evaluated and classified in a panel of widely studied colorectal cancer cell lines. "Class I" genes were uniformly induced by p53 in all cell lines; "class II" genes were induced in a subset of the lines; and "class III" genes were not induced in any of the lines. These genes were also distinguished by the timing of their induction, their induction by clinically relevant chemotherapeutic agents, the absolute requirement for p53 in this induction, and their inducibility by p73, a p53 homolog. The results revealed substantial heterogeneity in the transcriptional responses to p53, even in cells derived from a single epithelial cell type, and pave the way to a deeper understanding of p53 tumor suppressor action.

[1]  K. Kinzler,et al.  Requirement for p53 and p21 to sustain G2 arrest after DNA damage. , 1998, Science.

[2]  W. Kaelin,et al.  p73 is a human p53-related protein that can induce apoptosis , 1997, Nature.

[3]  L. Bracco,et al.  The requirement for the p53 proline‐rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression , 1998, The EMBO journal.

[4]  P. Jeffrey,et al.  Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. , 1994, Science.

[5]  M. Fiscella,et al.  A p53-independent Pathway for Activation of WAF1/CIP1 Expression Following Oxidative Stress * , 1995, The Journal of Biological Chemistry.

[6]  K. Dameron,et al.  Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. , 1994, Science.

[7]  Bert Vogelstein,et al.  p53 function and dysfunction , 1992, Cell.

[8]  Y. Yamauchi,et al.  Improved dicistronic mRNA expression vectors for efficient selection of transfectants highly expressing foreign genes. , 1996, BioTechniques.

[9]  Tony Pawson,et al.  Signaling Networks—Do All Roads Lead to the Same Genes? , 1999, Cell.

[10]  C. Prives,et al.  The p53 pathway , 1999, The Journal of pathology.

[11]  N. Pavletich,et al.  Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms , 1995, Science.

[12]  K. Kinzler,et al.  DNA methylation and genetic instability in colorectal cancer cells. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[13]  A. Levine.  p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[14]  M. Oren,et al.  p53 and apoptosis. , 2007, Seminars in cancer biology.

[15]  Carissa A. Sanchez,et al.  A p53-dependent mouse spindle checkpoint , 1995, Science.

[16]  K. Kinzler,et al.  A model for p53-induced apoptosis , 1997, Nature.

[17]  W. El-Deiry,et al.  Regulation of p53 downstream genes. , 1998, Seminars in cancer biology.

[18]  K. Kinzler,et al.  Genetic instability in colorectal cancers , 1997, Nature.

[19]  K. Kinzler,et al.  Disruption of p53 in human cancer cells alters the responses to therapeutic agents. , 1999, The Journal of clinical investigation.

[20]  D. Shibata,et al.  Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation , 1994, Nature Genetics.

[21]  K. Vousden,et al.  Mechanisms of p53-mediated apoptosis , 1999, Cellular and Molecular Life Sciences CMLS.

[22]  M. Oren.  Relationship of p53 to the control of apoptotic cell death. , 1994, Seminars in cancer biology.

[23]  G. Lozano,et al.  Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. , 1990, Science.

[24]  R. Jackson,et al.  Initiation of encephalomyocarditis virus RNA translation: the authentic initiation site is not selected by a scanning mechanism. , 1990, The EMBO journal.

[25]  Bert Vogelstein,et al.  Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21 , 1996, Nature.

[26]  S. Fields,et al.  Presence of a potent transcription activating sequence in the p53 protein. , 1990, Science.

[27]  T. Jacks,et al.  Characterization of the p53-Dependent Postmitotic Checkpoint following Spindle Disruption , 1998, Molecular and Cellular Biology.

[28]  A. Yang,et al.  Monoallelically Expressed Gene Related to p53 at 1p36, a Region Frequently Deleted in Neuroblastoma and Other Human Cancers , 1997, Cell.

[29]  M. Gossen,et al.  Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. , 1992, Proceedings of the National Academy of Sciences of the United States of America.