Zinc binding and redox control of p53 structure and function.

The p53 protein is a tumor suppressor often inactivated in cancer, which controls cell proliferation and survival through several coordinated pathways. The p53 protein is induced in response to many forms of cellular stress, genotoxic or not. p53 is a zinc-binding protein containing several reactive cysteines, and its key biochemical property, sequence-specific DNA binding, is dependent upon metal and redox regulation in vitro. In this review, we describe the main features of p53 as a metalloprotein and we discuss how metal binding and oxidation-reduction may affect p53 activity in vivo. In particular, we stress the possible involvement of thioredoxin, Ref-1 (redox factor 1), and metallothionein in the control of p53 protein conformation and activity. Furthermore, we also review the available evidence on the role of p53 as a transactivator or transrepressor of genes involved in the production and control of reactive oxygen intermediates. Overall, these data indicate that p53 lies at the center of a network of complex redox interactions. In this network, p53 can control the timely production of reactive oxygen intermediates (e.g., to initiate apoptosis), but this activity is itself under the control of changes in metal levels and in cellular redox status. This redox sensitivity may be one of the biochemical mechanisms by which p53 acts as a "sensor" of multiple forms of stress.

[1]  J. Milner,et al.  A Hitchhiker’s Guide to the NIEHS Strategic Plan , 1990, British Journal of Cancer.

[2]  G. Zambetti,et al.  ei24, a p53 Response Gene Involved in Growth Suppression and Apoptosis , 2000, Molecular and Cellular Biology.

[3]  P. Hainaut,et al.  Cadmium Induces Conformational Modifications of Wild-type p53 and Suppresses p53 Response to DNA Damage in Cultured Cells* , 1999, The Journal of Biological Chemistry.

[4]  R. von Harsdorf,et al.  p53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c‐independent apoptosis blocked by Bcl‐2 , 1999, The EMBO journal.

[5]  C. Prives,et al.  Ref‐1 regulates the transactivation and pro‐apoptotic functions of p53 in vivo , 1999, The EMBO journal.

[6]  L. Neckers,et al.  Stabilization of wild-type p53 by hypoxia-inducible factor 1α , 1998, Nature.

[7]  G. Wahl,et al.  p53 regulation by post-translational modification and nuclear retention in response to diverse stresses , 1999, Oncogene.

[8]  P. Hainaut,et al.  Regulation of p53 by metal ions and by antioxidants: dithiocarbamate down-regulates p53 DNA-binding activity by increasing the intracellular level of copper , 1997, Molecular and cellular biology.

[9]  S. Orrenius,et al.  Demonstration of nuclear compartmentalization of glutathione in hepatocytes. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[10]  T. Fojo,et al.  p53 Inhibits Hypoxia-inducible Factor-stimulated Transcription* , 1998, The Journal of Biological Chemistry.

[11]  Y. Yamaoka,et al.  Possible association of thioredoxin and p53 in breast cancer. , 2000, Immunology letters.

[12]  Yi Sun,et al.  Activation of p53 transcriptional activity by 1,10-phenanthroline, a metal chelator and redox sensitive compound , 1997, Oncogene.

[13]  W. Kaelin.  The p53 gene family , 1999, Oncogene.

[14]  D. Parks,et al.  Redox state regulates binding of p53 to sequence-specific DNA, but not to non-specific or mismatched DNA. , 1997, Nucleic acids research.

[15]  A. Abdel-Mageed,et al.  Activation of nuclear factor kappaB: potential role in metallothionein-mediated mitogenic response. , 1998, Cancer research.

[16]  N. Pavletich,et al.  Structure of the p53 Tumor Suppressor Bound to the Ankyrin and SH3 Domains of 53BP2 , 1996, Science.

[17]  J. Coleman,et al.  Zinc proteins: enzymes, storage proteins, transcription factors, and replication proteins. , 1992, Annual review of biochemistry.

[18]  V. Reinke,et al.  The tumor suppressor p53 regulates its own transcription , 1993, Molecular and cellular biology.

[19]  C. Harris,et al.  Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

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

[21]  Gregory L. Verdine,et al.  Structure of the human NF‐κB p52 homodimer‐DNA complex at 2.1 Å resolution , 1997 .

[22]  J Milner,et al.  Modulation by copper of p53 conformation and sequence-specific DNA binding: role for Cu(II)/Cu(I) redox mechanism. , 1995, Oncogene.

[23]  M. Swaroop,et al.  Transcriptional Activation of the Human Glutathione Peroxidase Promoter by p53* , 1999, The Journal of Biological Chemistry.

[24]  P. Hainaut,et al.  Nitric oxide nitrates tyrosine residues of tumor-suppressor p53 protein in MCF-7 cells. , 2000, Biochemical and biophysical research communications.

[25]  K. Mori,et al.  AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[26]  K. Mori,et al.  Distinct Roles of Thioredoxin in the Cytoplasm and in the Nucleus , 1999, The Journal of Biological Chemistry.

[27]  H. Kung,et al.  Mouse peroxiredoxin V is a thioredoxin peroxidase that inhibits p53-induced apoptosis. , 2000, Biochemical and biophysical research communications.

[28]  D. Beach,et al.  A mutation in a thioredoxin reductase homolog suppresses p53-induced growth inhibition in the fission yeast , 1996 .

[29]  T. Jacks,et al.  Identification and cloning of EI24, a gene induced by p53 in etoposide-treated cells. , 1996, Oncogene.

[30]  P. Hainaut,et al.  Redox modulation of p53 conformation and sequence-specific DNA binding in vitro. , 1993, Cancer research.

[31]  M. Hollstein,et al.  p53 and human cancer: the first ten thousand mutations. , 2000, Advances in cancer research.

[32]  B. Vallée.  Introduction to metallothionein. , 1991, Methods in enzymology.

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

[34]  Elias S. J. Arnér,et al.  Physiological functions of thioredoxin and thioredoxin reductase. , 2000, European journal of biochemistry.

[35]  B. Vallee,et al.  Cell cycle regulation of metallothionein in human colonic cancer cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[36]  K. Chung,et al.  Novel biphasic effect of pyrrolidine dithiocarbamate on neuronal cell viability is mediated by the differential regulation of intracellular zinc and copper ion levels, NF‐κb, and MAP kinases , 2000, Journal of neuroscience research.

[37]  G. D. Pearson,et al.  Deletion of the Saccharomyces cerevisiae TRR1 Gene Encoding Thioredoxin Reductase Inhibits p53-dependent Reporter Gene Expression* , 1998, The Journal of Biological Chemistry.

[38]  C. Kim,et al.  Pyrithione, a Zinc Ionophore, Inhibits NF-κB Activation , 1999 .

[39]  T. Sakai,et al.  Thioredoxin-dependent Redox Regulation of p53-mediated p21 Activation* , 1999, The Journal of Biological Chemistry.

[40]  J. Berg,et al.  Metal-dependent folding of a single zinc finger from transcription factor IIIA. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[41]  N. Copeland,et al.  The p53-inducible gene EI24/PIG8 localizes to human chromosome 11q23 and the proximal region of mouse chromosome 9 , 2000, Cytogenetic and Genome Research.

[42]  B. Vogelstein,et al.  p53-dependent expression of PIG3 during proliferation, genotoxic stress, and reversible growth arrest. , 2000, Cancer letters.

[43]  P. Hainaut,et al.  Redox signalling and transition metals in the control of the p53 pathway. , 2000, Biochemical pharmacology.

[44]  M. Moroni,et al.  In vitro antioxidant properties of amifostine (WR-2721, Ethyol) , 2000, Cancer Chemotherapy and Pharmacology.

[45]  W. Maret,et al.  Zinc and Health: Current Status and Future Directions The Function of Zinc Metallothionein: A Link between Cellular Zinc and Redox State 1,2 , 2000 .

[46]  M. V. Heiden,et al.  Redox regulation of p53 during hypoxia , 2000, Oncogene.

[47]  P. Hainaut,et al.  Modulation of p53 protein conformation and DNA‐binding activity by intracellular chelation of zinc , 1998, Molecular carcinogenesis.

[48]  T. Curran,et al.  Redox regulation of AP-1: a link between transcription factor signaling and DNA repair. , 1996, Advances in experimental medicine and biology.

[49]  P. Hainaut,et al.  The cytoprotective aminothiol WR1065 activates p21waf-1 and down regulates cell cycle progression through a p53-dependent pathway , 2000, Oncogene.

[50]  E. Paleček,et al.  Effect of transition metals on binding of p53 protein to supercoiled DNA and to consensus sequence in DNA fragments , 1999, Oncogene.

[51]  J Milner,et al.  Flexibility: the key to p53 function? , 1995, Trends in biochemical sciences.

[52]  H. Pahl,et al.  Regulation of the transcription factors NF-kappa B and AP-1 by redox changes. , 1994, Chemico-biological interactions.

[53]  E. Feinstein,et al.  Stress-induced secretion of growth inhibitors: a novel tumor suppressor function of p53 , 1998, Oncogene.

[54]  T. Curran,et al.  Identification of redox/repair protein Ref-1 as a potent activator of p53. , 1997, Genes & development.

[55]  P. Tegtmeyer,et al.  Role of cysteine residues in regulation of p53 function , 1995, Molecular and cellular biology.

[56]  C. Pabo,et al.  The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots. , 1993, Genes & development.

[57]  T. Rea,et al.  Identification of the genes responsive to etoposide‐induced apoptosis: application of DNA chip technology , 1999, FEBS letters.

[58]  T. Curran,et al.  Redox Regulation of Ap-1 , 1996 .

[59]  N. Altorki,et al.  Inhibition of Cyclooxygenase-2 Gene Expression by p53* , 1999, The Journal of Biological Chemistry.

[60]  D. Lane,et al.  Activation of the cryptic DNA binding function of mutant forms of p53. , 1993, Nucleic acids research.

[61]  J Milner,et al.  A structural role for metal ions in the "wild-type" conformation of the tumor suppressor protein p53. , 1993, Cancer research.

[62]  T. Curran,et al.  The redox and DNA-repair activities of Ref-1 are encoded by nonoverlapping domains. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[63]  C. Prives,et al.  p53: puzzle and paradigm. , 1996, Genes & development.

[64]  G. D. Pearson,et al.  The human p53 negative regulatory domain mediates inhibition of reporter gene transactivation in yeast lacking thioredoxin reductase. , 1999, Cancer research.

[65]  Hsiao-Huei Wu,et al.  Pyrrolidine Dithiocarbamate Prevents p53 Activation and Promotes p53 Cysteine Residue Oxidation* , 1998, The Journal of Biological Chemistry.

[66]  P. Hainaut,et al.  Nitric oxide prevents gamma-radiation-induced cell cycle arrest by impairing p53 function in MCF-7 cells. , 2001, Biochemical and biophysical research communications.

[67]  J. Piette,et al.  Multiple redox regulation in NF-kappaB transcription factor activation. , 1997, Biological chemistry.

[68]  T. Curran,et al.  Redox activation of Fos‐Jun DNA binding activity is mediated by a DNA repair enzyme. , 1992, The EMBO journal.

[69]  W. Maret,et al.  Thiolate ligands in metallothionein confer redox activity on zinc clusters. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[70]  J. Lotem,et al.  Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[71]  P. Hainaut,et al.  Nitric oxide induces conformational and functional modifications of wild-type p53 tumor suppressor protein. , 1997, Cancer research.

[72]  M. Kelley,et al.  Going APE over ref-1. , 2000, Mutation research.

[73]  Catherine Méplan,et al.  Metalloregulation of the tumor suppressor protein p53: zinc mediates the renaturation of p53 after exposure to metal chelators in vitro and in intact cells , 2000, Oncogene.

[74]  J. Hall,et al.  Radiation, DNA damage and cancer. , 1999, Molecular medicine today.

[75]  C. Delphin,et al.  Characterization of baculovirus recombinant wild-type p53 , 1994 .

[76]  H. Wu,et al.  NF-kappa B activation of p53. A potential mechanism for suppressing cell growth in response to stress. , 1994, The Journal of biological chemistry.

[77]  T. Graeber,et al.  Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status , 1994, Molecular and cellular biology.