Mutations in the p53 tumour-suppressor gene are the most frequently observed genetic lesions in human cancers. To investigate the role of the p53 gene in mammalian development and tumorigenesis, a null mutation was introduced into the gene by homologous recombination in murine embryonic stem cells. Mice homozygous for the null allele appear normal but are prone to the spontaneous development of a variety of neoplasms by 6 months of age. These observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.

Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours

The cell cycle is composed of a series of steps which can be negatively or positively regulated by various factors. Chief among the negative regulators is the p53 protein. Alteration or inactivation of p53 by mutation, or by its interactions with oncogene products of DNA tumour viruses, can lead to cancer. These mutations seem to be the most common genetic change in human cancers.

The p53 tumour suppressor gene

Analysis of membrane and surface protein sequences with the hydrophobic moment plot.

https://www.cell.com/cell/pdf/0092-8674(88)90559-4.pdf

SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene

Point mutations in the p53 gene are the most frequently identified genetic change in human cancer. They convert murine p53 from a tumour suppressor gene into a dominant transforming oncogene able to immortalize primary cells and bring about full transformation in combination with an activated ras gene. In both the human and murine systems the mutations lie in regions of p53 conserved from man to Xenopus. We have developed a monoclonal antibody to p53 designated PAb240 which does not immunoprecipitate wild type p53. A series of different p53 mutants all react more strongly with PAb240 than with PAb246. The PAb240 reactive form of p53 cannot bind to SV40 large T antigen but does bind to HSP70. In contrast, the PAb246 form binds to T antigen but not to HSP70. PAb240 recognizes all forms of p53 when they are denatured. It reacts with all mammalian p53 and chicken p53 in immunoblots. We propose that immunoprecipitation of p53 by PAb240 is diagnostic of mutation in both murine and human systems and suggest that the different point mutations which convert p53 from a recessive to a dominant oncogene exert a common conformational effect on the protein. This conformational change abolishes T antigen binding and promotes self-oligomerization. These results are consistent with a dominant negative model where mutant p53 protein binds to and neutralizes the activity of p53 in the wild type conformation.

Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form.

The HLA–DR and related antigens are the major cell-surface glycoproteins identified so far as involved in regulation of the immune response in humans1. Here we present and discuss the sequence of cloned cDNA copies of the mRNA for the HLA–DR α-chain2. The sequence is 1,195 nucleotides long, with one open reading frame encoding a 254 amino acid primary translation product. After cleavage of the signal sequence this yields a mature polypeptide of 229 residues. Four introns have been located within the corresponding genomic sequence revealing a correlation between the protein domain structure and the genomic exon organization. Analysis of the HLA–DR α-chain amino acid sequence shows a clear homology with HLA–ABC, β2-microglobulin and immunoglobulin domains.

/pdf/sequence-of-an-hla-dr-alpha-chain-cdna-clone-and-intron-exon-2nlktlsv9z.pdf

Sequence of an HLA-DR alpha-chain cDNA clone and intron-exon organization of the corresponding gene.

Transactivation of the p53 oncogene by E1a gene products.

Sequence divergence of rainbow trout protamine mRNAs; comparison of coding and non-coding nucleotide sequences in three protamine cDNA plasmids

Sequence divergence of rainbow trout protamine mRNAs; comparison of coding and non-coding nucleotide sequences in three protamine cDNA plasmids.

Ability ofp53andtheAdenovirus Elb58-Kilodalton Protein To Forma ComplexIsDetermined byp53

p53 is a cellular phosphoprotein that is present at elevated concentrations in cells transformed by different agents. p53 complementary DNA expression-constructs immortalize primary cells in vitro and co-operate with an activated ras oncogene in malignant transformation. Several reports have implicated p53 in mammalian cell cycle control and specifically with events occurring at the G0-G1 boundary. p53 forms specific complexes with simian virus 40 (SV40) large-T antigen, and such complexes are found associated with both replicating and mature SV40 DNA in lytically infected cells. In an accompanying paper Gannon and Lane report that in in vitro plate-binding assays, mouse p53 can displace polymerase alpha from complex with T-antigen. We have examined the in vivo consequences of expressing wild-type and mutant p53 proteins from other species in SV40-transformed monkey cells. We report here that expression of mouse p53 results in a substantial and selective inhibition of SV40 origin-dependent DNA replication. In addition to any function in the G0-G1 transition, the data presented suggest that p53 may affect directly the initiation or maintenance of replicative DNA synthesis.

Mouse p53 inhibits SV40 origin-dependent DNA replication.

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