Oligonucleotide microarrays were employed to quantitate mRNA levels from a large number of genes regulated by the p53 transcription factor. Responses to DNA damage and to zinc-inducible p53 were compared for their transcription patterns in cell culture. A cluster analysis of these data demonstrates that genes induced by gamma radiation, UV radiation, and the zinc-induced p53 form distinct sets and subsets with a few genes in common to all these treatments. Cell type- or cell line-specific p53 responses were detected. When p53 proteins were induced with zinc, the kinetics of induction or repression of mRNAs from p53-responsive genes fell into eight distinct classes, five different kinetics of induction, and three different kinetics of repression. In addition, low levels of p53 in a cell induced or repressed only a subset of genes observed at higher p53 levels. The results of this study demonstrate that the nature of the p53 response in diverse mRNA species depends on the levels of p53 protein in a cell, the type of inducing agent or event, and the cell type employed. Of 6000 genes examined for p53 regulatory responses, 107 induced and 54 repressed genes fell into categories of apoptosis and growth arrest, cytoskeletal functions, growth factors and their inhibitors, extracellular matrix, and adhesion genes.

/pdf/analysis-of-p53-regulated-gene-expression-patterns-using-hps9bkgx4m.pdf

Analysis of p53-regulated gene expression patterns using oligonucleotide arrays

Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis

Esophageal cancer (EC) ranks sixth in cancer death. To explore its genetic origins, we performed exomic sequencing on 11 adenocarcinomas (EAC) and 12 squamous cell carcinomas (ESCCs) from the United States. Interestingly, inactivating mutations of NOTCH1 were identified in 21% of ESCCs but not in EACs. There was a substantial disparity in the spectrum of mutations, with more indels in ESCCs, A:T>C:G transversions in EACs, and C:G>G:C transversions in ESCCs (p<0.0001). Notably, NOTCH1 mutations were more frequent in North American ESCCs (11 of 53 cases) than in ESCCs from China (1 of 48 cases). A parallel analysis found that most mutations in EACs were already present in matched Barrett's esophagus (BE). These discoveries highlight key genetic differences between EAC and ESCC, American and Chinese ESCC, and suggest that NOTCH1 is a tumor suppressor gene in the esophagus. Finally, we provide a genetic basis for the evolution of EACs from BE.

https://cancerdiscovery.aacrjournals.org/content/candisc/2/10/899.full.pdf

Comparative genomic analysis of esophageal adenocarcinoma and squamous cell carcinoma

The p53 gene is a critical tumor suppressor that is inactivated in a majority of cancers. The central role of p53 in response to stresses such as DNA damage, hypoxia, and oncogene activation underlies this high frequency of negative selection during tumorigenic transformation. Mutations in p53 disrupt checkpoint responses to DNA damage and result in the potential for destabilization of the genome. Consistent with this, p53 mutant cells have been shown to accumulate genomic alterations in cell culture, mouse models, and some human tumors. The relationship between p53 mutation and genomic instability in human osteosarcoma is addressed in this report. Similar to some other primary human tumors, the mutation of p53 correlates significantly with the presence of high levels of genomic instability in osteosarcomas. Surprisingly, osteosarcomas harboring an amplification of the HDM2 oncogene, which inhibits the tumor-suppressive properties of p53, do not display high levels of genomic instability. These results demonstrate that the inactivation of p53 in osteosarcomas directly by mutation versus indirectly by HDM2 amplification may have different cellular consequences with respect to the stability of the genome.

https://www.pnas.org/content/pnas/100/20/11547.full.pdf

The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Despite significant clinical improvements over the past several decades through the use of combination chemotherapy and surgery, patients with metastatic or recurrent disease continue to have a very poor prognosis. Therefore, there is a continued need to study and understand the basic biology of osteosarcoma in order to devise more targeted and rational therapeutic strategies and ultimately to improve survival for these patients. This article reviews several aspects of osteosarcoma biology where data exist to suggest that specific pathways may play a role in the pathogenesis of this tumor. These areas include host genetic predispositions, tumor cytogenetics, molecular genetics (including the Rb, p53, RECQ helicase, and telomere pathways), and metastatic factors (ezrin, annexin 2, chemokine receptor 4, Fas/FasL pathways) that may contribute to both the initiation and the progression of tumor formation. Understanding the mechanisms of and interactions between the various molecular pathways that play a role in osteosarcoma pathogenesis may eventually lead to a more rational strategy for devising therapies targeted specifically toward these pathways.

Biology of osteogenic sarcoma.

Mutational Spectra and Immunohistochemical Analyses of p53 in Human Cancers

La presente invention concerne des procedes et des compositions pour moduler la senescence cellulaire et la proliferation cellulaire avec des isoformes de la proteine suppresseur de tumeur p53. Les procedes et les compositions de l'invention sont utiles pour inhiber la croissance cellulaire cancereuse ou pour generer des populations de cellules a des fins de regeneration tissulaire par modulation de la senescence et de la proliferation cellulaires.

Applications thérapeutiques des isoformes p53 en médecine régénératrice, pour lutter contre le vieillissement et le cancer

The present invention is directed to therapies that modulate naturally occurring p53 isoforms for the treatment of diseases of premature aging.

Extension of replicative lifespan in diseases of premature aging using p53 isoforms

The present invention is directed to therapies that modulate expression or activity a naturally occurring p53 isoform for the treatment of a neurodegenerative disorder in which astrocytes are dysfunctional.

David P. Lane

Papers

Mutational Spectra and Immunohistochemical Analyses of p53 in Human Cancers

Applications thérapeutiques des isoformes p53 en médecine régénératrice, pour lutter contre le vieillissement et le cancer

Extension of replicative lifespan in diseases of premature aging using p53 isoforms

Enhancing astrocyte neuroprotective functions using p53 isoforms