Life and death by P53

p53 is a multifunctional protein which plays a role in modulating gene transcription, policing cell cycle checkpoints, activating apoptosis, controlling DNA replication and repair, maintaining genomic stability and responding to genetic insults. Mutation of the p53 gene confers the single greatest known selective advantage favoring cancer formation. Point mutations result not only in the loss of tumor suppressor functions, but also in the gain of tumor promotion functions. These dual circumstances may be unique to p53 and, in part, could explain the relatively powerful force behind this selection pressure. General mechanisms of gain of function by mutated p53 may include alteration in transcriptional modulation and newly acquired targets for transcriptional regulation and protein binding. Despite the direct significance of p53 mutations, loss of the remaining wild‐type allele is usually required for the formation of tumors in the natural setting. Novel applications of the basic scientific knowledge of p53 could lead to an improvement in cancer treatment, hopefully in the not so distant future.

[1]  L. Cox,et al.  A direct effect of activated human p53 on nuclear DNA replication. , 1995, The EMBO journal.

[2]  T. Leslie Youd,et al.  Structural Aspects , 1995 .

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

[4]  Lawrence A. Donehower,et al.  A mutant p53 transgene accelerates tumour development in heterozygous but not nullizygous p53–deficient mice , 1995, Nature Genetics.

[5]  E. Androphy,et al.  The domain of p53 required for binding HPV 16 E6 is separable from the degradation domain. , 1995, Oncogene.

[6]  J. Milner,et al.  Structural and kinetic analysis of p53-DNA complexes and comparison of human and murine p53. , 1995, Oncogene.

[7]  D. Housman,et al.  p53 status and the efficacy of cancer therapy in vivo. , 1994, Science.

[8]  J. Roth,et al.  Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model. , 1994, Journal of the National Cancer Institute.

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

[10]  Y. Chen,et al.  Hot-spot p53 mutants interact specifically with two cellular proteins during progression of the cell cycle , 1994, Molecular and cellular biology.

[11]  C. Harris,et al.  Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. , 1994, Cancer research.

[12]  H. Shepard,et al.  Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer. , 1994, Human gene therapy.

[13]  S. Lowe,et al.  p53-Dependent apoptosis suppresses tumor growth and progression in vivo , 1994, Cell.

[14]  J. E. Stenger,et al.  p53 domains: structure, oligomerization, and transformation , 1994, Molecular and cellular biology.

[15]  M. Karin,et al.  p53-Dependent apoptosis in the absence of transcriptional activation of p53-target genes , 1994, Nature.

[16]  A. Gronenborn,et al.  High-resolution structure of the oligomerization domain of p53 by multidimensional NMR. , 1994, Science.

[17]  R. Brown,et al.  Cell cycle arrests and radiosensitivity of human tumor cell lines: dependence on wild-type p53 for radiosensitivity. , 1994, Cancer research.

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

[19]  M. Fukayama,et al.  Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. , 1994, Cancer research.

[20]  I. Runnebaum,et al.  Wild-type p53 suppresses the malignant phenotype in breast cancer cells containing mutant p53 alleles. , 1994, Anticancer research.

[21]  J. Roth,et al.  Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene. , 1994, Cancer research.

[22]  K. Kinzler,et al.  Sequence-specific transcriptional activation is essential for growth suppression by p53. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[23]  S. Friend,et al.  Equal transcription of wild-type and mutant p53 using bicistronic vectors results in the wild-type phenotype. , 1994, Cancer research.

[24]  J. E. Stenger,et al.  p53 domains: identification and characterization of two autonomous DNA-binding regions. , 1993, Genes & development.

[25]  X. Chen,et al.  A proteolytic fragment from the central region of p53 has marked sequence-specific DNA-binding activity when generated from wild-type but not from oncogenic mutant p53 protein. , 1993, Genes & development.

[26]  S. Elledge,et al.  The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases , 1993, Cell.

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

[28]  J. Shay,et al.  Inactive p53 mutants may enhance the transcriptional activity of wild-type p53. , 1993, Cancer research.

[29]  K. Kohn,et al.  Role of the p53 tumor suppressor gene in cell cycle arrest and radiosensitivity of Burkitt's lymphoma cell lines. , 1993, Cancer research.

[30]  J. Roth,et al.  A retroviral wild-type p53 expression vector penetrates human lung cancer spheroids and inhibits growth by inducing apoptosis. , 1993, Cancer research.

[31]  E. Winchester,et al.  Inhibition of DNA replication factor RPA by p53 , 1993, Nature.

[32]  M. Scheffner,et al.  Functional domains of wild-type and mutant p53 proteins involved in transcriptional regulation, transdominant inhibition, and transformation suppression , 1993, Molecular and cellular biology.

[33]  J. Berzofsky,et al.  A mutant p53 tumor suppressor protein is a target for peptide-induced CD8+ cytotoxic T-cells. , 1993, Cancer research.

[34]  K. Lukacs,et al.  Tumor cells transfected with a bacterial heat-shock gene lose tumorigenicity and induce protection against tumors , 1993, The Journal of experimental medicine.

[35]  A. Levine,et al.  The p53-mdm-2 autoregulatory feedback loop. , 1993, Genes & development.

[36]  S. Pulst,et al.  Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2 , 1993, Nature.

[37]  S. Fields,et al.  Use of the two-hybrid system to identify the domain of p53 involved in oligomerization. , 1993, Oncogene.

[38]  Yi-Song Wang,et al.  Wild-type p53 induces apoptosis in a Burkitt lymphoma (BL) line that carries mutant p53. , 1993, Oncogene.

[39]  J. Pipas,et al.  Specific repression of TATA-mediated but not initiator-mediated transcription by wild-type p53 , 1993, Nature.

[40]  M. Melamed,et al.  Induction of DNA strand breaks associated with apoptosis during treatment of leukemias. , 1993, Leukemia.

[41]  C. Woodworth,et al.  Overexpression of wild-type p53 alters growth and differentiation of normal human keratinocytes but not human papillomavirus-expressing cell lines. , 1993, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[42]  C. Purdie,et al.  Thymocyte apoptosis induced by p53-dependent and independent pathways , 1993, Nature.

[43]  Bert Vogelstein,et al.  Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53 , 1993, Nature.

[44]  W. Lee,et al.  Tumor suppressor activity of RB and p53 genes in human breast carcinoma cells. , 1993, Oncogene.

[45]  E. Stanbridge,et al.  Growth suppression mediated by transfection of p53 in Hut292DM human lung cancer cells expressing endogenous wild-type p53 protein. , 1992, Cancer research.

[46]  G. Zambetti,et al.  Wild-type p53 binds to the TATA-binding protein and represses transcription. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[47]  R. Reddel,et al.  Effects of exogenous wild-type p53 on a human lung carcinoma cell line with endogenous wild-type p53. , 1992, Experimental cell research.

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

[49]  M. Oren,et al.  The gene for the rat heat-shock cognate, hsc70, can suppress oncogene-mediated transformation. , 1992, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[50]  M. Subler,et al.  Modulation of cellular and viral promoters by mutant human p53 proteins found in tumor cells , 1992, Journal of virology.

[51]  Thea D. Tlsty,et al.  Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53 , 1992, Cell.

[52]  G. Wahl,et al.  Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles , 1992, Cell.

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

[54]  M. Kastan,et al.  Wild-type p53 is a cell cycle checkpoint determinant following irradiation. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[55]  M. Remm,et al.  A C-terminal alpha-helix plus basic region motif is the major structural determinant of p53 tetramerization. , 1992, Oncogene.

[56]  P. Friedman,et al.  Wild-type p53 activates transcription in vitro , 1992, Nature.

[57]  A. Levine,et al.  Wild-type p53 mediates positive regulation of gene expression through a specific DNA sequence element. , 1992, Genes & development.

[58]  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.

[59]  W. Blattner,et al.  Detection of both mutant and wild-type p53 protein in normal skin fibroblasts and demonstration of a shared 'second hit' on p53 in diverse tumors from a cancer-prone family with Li-Fraumeni syndrome. , 1992, Oncogene.

[60]  T Takahashi,et al.  Wild-type but not mutant p53 suppresses the growth of human lung cancer cells bearing multiple genetic lesions. , 1992, Cancer research.

[61]  L. Donehower,et al.  Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours , 1992, Nature.

[62]  I. Pastan,et al.  Modulation of activity of the promoter of the human MDR1 gene by Ras and p53. , 1992, Science.

[63]  G. Lozano,et al.  Analysis of p53 mutants for transcriptional activity , 1991, Molecular and cellular biology.

[64]  B. Vogelstein,et al.  Participation of p53 protein in the cellular response to DNA damage. , 1991, Cancer research.

[65]  Y. Chen,et al.  Expression of wild-type p53 in human A673 cells suppresses tumorigenicity but not growth rate. , 1991, Oncogene.

[66]  B. Vogelstein,et al.  Growth suppression of human breast cancer cells by the introduction of a wild-type p53 gene. , 1991, Oncogene.

[67]  A. Kimchi,et al.  Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6 , 1991, Nature.

[68]  K. Kinzler,et al.  Identification of p53 as a sequence-specific DNA-binding protein , 1991, Science.

[69]  J. Milner,et al.  Cotranslation of activated mutant p53 with wild type drives the wild-type p53 protein into the mutant conformation , 1991, Cell.

[70]  C. Nelson,et al.  Adenovirus E1b-58 kD antigen binds to p53 during infection of rodent cells: evidence for an N-terminal binding site on p53. , 1991, Oncogene.

[71]  S. Benchimol,et al.  Expression of wild-type p53 is not compatible with continued growth of p53-negative tumor cells , 1991, Molecular and cellular biology.

[72]  Yumay Chen,et al.  Genetic mechanisms of tumor suppression by the human p53 gene , 1990, Science.

[73]  V. Rotter,et al.  Nuclear accumulation of p53 protein is mediated by several nuclear localization signals and plays a role in tumorigenesis , 1990, Molecular and cellular biology.

[74]  B. Vogelstein,et al.  p53 functions as a cell cycle control protein in osteosarcomas , 1990, Molecular and cellular biology.

[75]  O. Halevy,et al.  Different tumor-derived p53 mutants exhibit distinct biological activities. , 1990, Science.

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

[77]  B. Vogelstein,et al.  Suppression of human colorectal carcinoma cell growth by wild-type p53. , 1990, Science.

[78]  E. Appella,et al.  Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild-type p53. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[79]  T. Soussi,et al.  Structural aspects of the p53 protein in relation to gene evolution. , 1990, Oncogene.

[80]  A. Levine,et al.  The p53 proto-oncogene can act as a suppressor of transformation , 1989, Cell.

[81]  P. Friedman,et al.  The murine p53 protein blocks replication of SV40 DNA in vitro by inhibiting the initiation functions of SV40 large T antigen , 1989, Cell.

[82]  A. Levine,et al.  Mutation is required to activate the p53 gene for cooperation with the ras oncogene and transformation , 1989, Journal of virology.

[83]  M. Oren,et al.  Oligomerization of oncoprotein p53 , 1988, Journal of virology.

[84]  J. Jenkins,et al.  Two distinct regions of the murine p53 primary amino acid sequence are implicated in stable complex formation with simian virus 40 T antigen , 1988, Journal of virology.

[85]  Rotter,et al.  Meth A fibrosarcoma cells express two transforming mutant p53 species. , 1988, Oncogene.

[86]  J. Jenkins,et al.  Mouse p53 inhibits SV40 origin-dependent DNA replication , 1987, Nature.

[87]  D. Lane,et al.  p53 and DNA polymerase α compete for binding to SV40 T antigen , 1987, Nature.

[88]  I. Herskowitz Functional inactivation of genes by dominant negative mutations , 1987, Nature.

[89]  L. Crawford,et al.  Characterization of the human p53 gene , 1986, Molecular and cellular biology.

[90]  V. Rotter,et al.  Reconstitution of p53 expression in a nonproducer Ab-MuLV-transformed cell line by transfection of a functional p53 gene , 1984, Cell.

[91]  J. Roth,et al.  In vivo molecular therapy with p53 adenovirus for microscopic residual head and neck squamous carcinoma. , 1995, Cancer research.

[92]  K. Kinzler,et al.  Oncogenic forms of p53 inhibit p53-regulated gene expression. , 1992, Science.

[93]  V. Rotter,et al.  Mutant p53 proteins bind DNA abnormally in vitro. , 1991, Oncogene.