Therapeutic potential of antisense oligodeoxynucleotides in downregulating p53 oncogenic mutations in cancers

Purpose of work  

Mutation of the p53 gene is the most common genetic alteration in human cancers. Our study proposes to rationally design a p53 antisense oligonucleotide (ASO) repository, which contains a series of ASOs containing single nucleotide differences to discriminate between each mutant and wild type (WT) p53.     

Impact of Alu repeats on the evolution of human p53 binding sites

Background  

The p53 tumor suppressor protein is involved in a complicated regulatory network, mediating expression of ~1000 human genes. Recent studies have shown that many p53 in vivo binding sites (BSs) reside in transposable repeats. The relationship between these BSs and functional p53 response elements (REs) remains unknown, however. We sought to understand whether the p53 REs also reside in transposable elements and particularly in the most-abundant Alu repeats.     

Absence of p53 in Clara cells favours multinucleation and loss of cell cycle arrest

Background  

The p53 oncosuppressor protein is a critical mediator of the response to injury in mammalian cells and is mutationally inactivated in the majority of lung malignancies. In this analysis, the effects of p53-deficiency were investigated in short-term primary cultures of murine bronchiolar Clara cells. Clara cells, isolated from gene-targeted p53-deficient mice, were compared to cells derived from wild type littermates.     

Glycerol restores heat-induced p53-dependent apoptosis of human glioblastoma cells bearing mutant p53

Background  

We have previously reported that glycerol acts as a chemical chaperone to restore the expression of WAF1 in some human cancer cell lines bearing mutant p53. Since the expression of WAF1 is up-regulated by activated wildtype p53, glycerol appears to restore wtp53 function. The aim of the present study is to examine the restoration of heat-induced p53-dependent apoptosis by glycerol in human glioblastoma cells (A-172) transfected with a vector carrying a mutant p53 gene (A-172/mp53 cells) or neo control vector (A-172/neo cells).     

Effect of hydroxyurea on the promoter occupancy profiles of tumor suppressor p53 and p73

Background  

The p53 tumor suppressor and its related protein, p73, share a homologous DNA binding domain, and mouse genetics studies have suggested that they have overlapping as well as distinct biological functions. Both p53 and p73 are activated by genotoxic stress to regulate an array of cellular responses. Previous studies have suggested that p53 and p73 independently activate the cellular apoptotic program in response to cytotoxic drugs. The goal of this study was to compare the promoter-binding activity of p53 and p73 at steady state and after genotoxic stress induced by hydroxyurea.     

P53 and Beta-Catenin Activity during Estrogen treatment of Osteoblasts

Background  

This study was undertaken to examine the relationship between the tumor suppressor gene p53 and the nuclear signaling protein beta-catenin during bone differentiation. Cross talk between p53 and beta-catenin pathways has been demonstrated and is important during tumorigenesis and DNA damage, where deregulation of beta catenin activates p53. In this study, we used estrogen treatment of osteoblasts as a paradigm to study the relationship between the two proteins during osteoblast differentiation.     

Differential regulation of p53 function by the N-terminal ΔNp53 and Δ113p53 isoforms in zebrafish embryos

Background  

The p53 protein family coordinates stress responses of cells and organisms. Alternative promoter usage and/or splicing of p53 mRNA gives rise to at least nine mammalian p53 proteins with distinct N- and C-termini which are differentially expressed in normal and malignant cells. The human N-terminal p53 variants contain either the full-length (FL), or a truncated (ΔN/Δ40) or no transactivation domain (Δ133) altogether. The functional consequences of coexpression of the different p53 isoforms are poorly defined. Here we investigated functional aspects of the zebrafish ΔNp53 ortholog in the context of FLp53 and the zebrafish Δ133p53 ortholog (Δ113p53) coexpressed in the developing embryo.     

Nuclear accumulation and activation of p53 in embryonic stem cells after DNA damage

Background  

P53 is a key tumor suppressor protein. In response to DNA damage, p53 accumulates to high levels in differentiated cells and activates target genes that initiate cell cycle arrest and apoptosis. Since stem cells provide the proliferative cell pool within organisms, an efficient DNA damage response is crucial.     

Occurrence of multipolar mitoses and association with Aurora-A/-B kinases and p53 mutations in aneuploid esophageal carcinoma cells

Background  

Aurora kinases and loss of p53 function are implicated in the carcinogenesis of aneuploid esophageal cancers. Their association with occurrence of multipolar mitoses in the two main histotypes of aneuploid esophageal squamous cell carcinoma (ESCC) and Barrett's adenocarcinoma (BAC) remains unclear. Here, we investigated the occurrence of multipolar mitoses, Aurora-A/-B gene copy numbers and expression/activation as well as p53 alterations in aneuploid ESCC and BAC cancer cell lines.     

HCCR-1, a novel oncogene,encodes a mitochondrial outer membrane protein and suppresses the UVC-induced apoptosis

Background  

The Human cervical cancer oncogene (HCCR-1) has been isolated as a human oncoprotein, and has shown strong tumorigenic features. Its potential role in tumorigenesis may result from a negative regulation of the p53 tumor suppressor gene.     

Targeting MDM2 by the small molecule RITA: towards the development of new multi-target drugs against cancer

Background  

The use of low-molecular-weight, non-peptidic molecules that disrupt the interaction between the p53 tumor suppressor and its negative regulator MDM2 has provided a promising alternative for the treatment of different types of cancer. Among these compounds, RITA (reactivation of p53 and induction of tumor cell apoptosis) has been shown to be effective in the selective induction of apoptosis, and this effect is due to its binding to the p53 tumor suppressor. Since biological systems are highly dynamic and MDM2 may bind to different regions of p53, new alternatives should be explored. On this basis, the computational "blind docking" approach was employed in this study to see whether RITA would bind to MDM2.     

p53 aberrations in low grade endometrioid carcinoma of the endometrium with nodal metastases: possible insights on pathogenesis discerned from immunohistochemistry

Background

TP53 mutations are rarely identified in low grade endometrioid carcinoma of the endometrium, and their pathogenic significance in such tumors is evidenced by the fact that TP53 aberrations have been associated with reduced recurrence-free survival in this subset of tumors. However, TP53 aberrations may not always represent a driving molecular event in a given endometrial cancer with a mutation. In this case study, the immunophenotype of a distinctive low grade endometrioid adenocarcinoma with an unusual pattern of lymph node metastases is used to explore the possible roles for underlying TP53-related molecular events in its pathogenesis.

Case presentation

A low grade endometrioid carcinoma, 9 cm in greatest dimension, with 35% invasion of the myometrial wall thickness, focal lymphovascular invasion, and metastases to 2 of 16 pelvic lymph nodes, was diagnosed in a 52-year-old woman. The endometrial tumor showed a p53-mutation (aberrant)-type immunohistochemical pattern in 40% of the tumor, but the rest of the tumor, as well as the foci of myometrial and lymphovascular invasion, were p53-wild type. Both lymph nodes with metastatic disease showed a distinct biphasic pattern, comprised of both p53-wild type and p53-aberrant areas in tumoral foci that were spatially apposed but not intermixed. Most p53-aberrant areas (at both the lymph nodes and the endometrium) showed a higher mitotic index and increased atypia as compared to the p53-wild type areas; both showed squamous differentiation. The p53-aberrant areas at both locations were also p16-diffusely positive, vimentin-positive, and estrogen/progesterone receptor-positive, whereas the p53-wild type areas showed an identical immunophenotype with the exception of being p16-mosaic positive. All components of the tumor at both the primary and metastatic sites showed loss of MSH2 and MSH6 and retained MLH/PMS2 expression.

Conclusions

The presence of p53-mutant and wild-type areas in multiple lymph nodes, coupled with the absence of a p53-aberrant immunophenotype in the myometrium-invasive or lymphovascular-invasive portions of the tumor, argues against the possibility that the TP53 mutation in this tumor is a driving event in its pathogenesis, at least regarding the metastatic process. This case illustrates how routine immunohistochemistry can provide important insights into underlying molecular events in cancers, exemplifies an uncommon co-existence of DNA mismatch repair protein deficiency and p53-aberrant immunophenotype in low-grade endometrioid carcinoma, illustrates morphologic differences between p53-aberrant and p53-wild type areas within in the same tumor, and is an exemplar of the emerging theory that lymph node metastases of endometrial cancer may be comprised of different subclones of the primary tumor.