PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes

Exposure of mammalian cells to hypoxia, radiation and certain chemotherapeutic agents promotes cell cycle arrest and/or apoptosis. Activation of p53 responsive genes is believed to play an important role in mediating such responses. In this study we identified a novel gene, PA26, which maps to chromosome 6q21 and encodes at least three transcript isoforms, of which two are differentially induced by genotoxic stress (UV, γ-irradiation and cytotoxic drugs) in a p53-dependent manner. A functional p53-responsive element was identified in the second intron of the PA26 gene, in consistence with a mechanism of transcriptional induction of the PA26 gene by p53. No clues to its functions were revealed by sequence analysis, although pronounced negative regulation by serum factors argues for a potential role of PA26 in growth regulation. Immunological analysis suggests that PA26 protein(s) is localized to the cell nucleus. Our results suggest that the PA26 gene is a novel p53 target gene with properties common to the GADD family of growth arrest and DNA damage-inducible stress-response genes, and, thus, a potential novel regulator of cellular growth.

[1]  M. Oren,et al.  Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential. , 1994, Genes & development.

[2]  D. Lane,et al.  p53, guardian of the genome , 1992, Nature.

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

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

[5]  B. Johansson,et al.  Cytogenetic evolution patterns in non-Hodgkin's lymphoma. , 1995, Blood.

[6]  T. Pejovic.  Genetic changes in ovarian cancer. , 1995, Annals of medicine.

[7]  L. Buckbinder,et al.  Gene regulation by temperature-sensitive p53 mutants: identification of p53 response genes. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[8]  P. Deloukas,et al.  A Gene Map of the Human Genome , 1996, Science.

[9]  A. Levine,et al.  The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation , 1992, Cell.

[10]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[11]  K. Kinzler,et al.  Definition of a consensus binding site for p53 , 1992, Nature Genetics.

[12]  I. Takenaka,et al.  Regulation of the Sequence-specific DNA Binding Function of p53 by Protein Kinase C and Protein Phosphatases (*) , 1995, The Journal of Biological Chemistry.

[13]  C. Morelli,et al.  Characterization of a 4-Mb region at chromosome 6q21 harboring a replicative senescence gene. , 1997, Cancer research.

[14]  H. Cavé,et al.  Delineation of a 6 cM commonly deleted region in childhood acute lymphoblastic leukemia on the 6q chromosomal arm , 1997, Leukemia.

[15]  I. Krantz,et al.  KILLER/DR5 is a DNA damage–inducible p53–regulated death receptor gene , 1997, Nature Genetics.

[16]  P. Meltzer,et al.  Amplification of a gene encoding a p53-associated protein in human sarcomas , 1992, Nature.

[17]  A. Levine,et al.  mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein , 1996, Molecular and cellular biology.

[18]  J. Fargnoli,et al.  Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents , 1989, Molecular and cellular biology.

[19]  J. Winkles,et al.  Serum- and polypeptide growth factor-inducible gene expression in mouse fibroblasts. , 1998, Progress in nucleic acid research and molecular biology.

[20]  P. Cohen,et al.  Insulin-like Growth Factor (IGF)-binding Protein-3 Induces Apoptosis and Mediates the Effects of Transforming Growth Factor-β1 on Programmed Cell Death through a p53- and IGF-independent Mechanism* , 1997, The Journal of Biological Chemistry.

[21]  A. Fornace,et al.  DNA damage-inducible transcripts in mammalian cells. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[22]  S. Baylin,et al.  p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3 , 1995, Nature Genetics.

[23]  S. Madden,et al.  Induction of cell growth regulatory genes by p53. , 1996, Cancer research.

[24]  P. Rao,et al.  Cytogenetic analysis of 11 squamous cell carcinomas of the head and neck. , 1994, Cancer genetics and cytogenetics.

[25]  P. O'Connor,et al.  Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. , 1994, Science.

[26]  R. Roeder,et al.  Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. , 1983, Nucleic acids research.

[27]  D. Israeli,et al.  A novel p53‐inducible gene, PAG608, encodes a nuclear zinc finger protein whose overexpression promotes apoptosis , 1997, The EMBO journal.

[28]  J. Brown,et al.  Karyotypic analysis of a heterogeneous human transitional cell carcinoma of the bladder. , 1994, Cancer genetics and cytogenetics.

[29]  John Calvin Reed,et al.  Tumor suppressor p53 is a direct transcriptional activator of the human bax gene , 1995, Cell.

[30]  B. Vogelstein,et al.  A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia , 1992, Cell.

[31]  A. Marchetti,et al.  Multiple regions of chromosome 6q affected by loss of heterozygosity in primary human breast carcinomas. , 1996, British Journal of Cancer.

[32]  S. Velasco-Miguel,et al.  Induction of the growth inhibitor IGF-binding protein 3 by p53 , 1995, Nature.

[33]  R. Berger,et al.  Identification of BTG2, an antiproliferative p53–dependent component of the DNA damage cellular response pathway , 1996, Nature Genetics.

[34]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[35]  Stephen N. Jones,et al.  Regulation of p53 stability by Mdm2 , 1997, Nature.

[36]  A. Tulpule,et al.  Similar biochemical changes associated with multidrug resistance in human breast cancer cells and carcinogen-induced resistance to xenobiotics in rats. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[37]  M. Santibanez-Koref,et al.  Allelic imbalance of chromosome 6q in ovarian tumours. , 1995, British Journal of Cancer.

[38]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[39]  M. Fiscella,et al.  Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[40]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[41]  C. Finlay,et al.  The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth , 1993, Molecular and cellular biology.

[42]  P. Shaw,et al.  Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[43]  A. Fornace,et al.  Genotoxic stress confers preferential and coordinate messenger RNA stability on the five gadd genes. , 1994, Cancer research.

[44]  M. Oren,et al.  Mdm2 promotes the rapid degradation of p53 , 1997, Nature.

[45]  J. Keene,et al.  Hel-N1: an autoimmune RNA-binding protein with specificity for 3' uridylate-rich untranslated regions of growth factor mRNAs. , 1993, Molecular and cellular biology.

[46]  D. Beach,et al.  Cyclin G is a transcriptional target of the p53 tumor suppressor protein. , 1994, The EMBO journal.

[47]  S. Velasco-Miguel,et al.  The p53 tumor suppressor targets a novel regulator of G protein signaling. , 1997, Proceedings of the National Academy of Sciences of the United States of America.