Mdm2 binds to the amino-terminus of p53 to induce its degradation and a single nucleotide polymorphism in the MDM2 promoter region (T309G) has been reported to increase the risk of several carcinomas, such as gastric cancer.
We sought to determine the relationship between somatic TP53 mutations, germline genotypes at TP53 codon 72 and MDM2 SNP309, and overall survival and response to chemotherapy in a large series of patients with ovarian and peritoneal carcinomas.
The risk of overall gastric carcinoma for SNP309 (G/G) was significantly increased when compared with T carriers (P = .039), especially carcinomas with extragastric tumors (P = .005), carcinoma with severe atrophic gastritis positive for PG assay (PG I level < 70 ng/mL and PG I/II < 3.0; P = .005), antral carcinoma (P = .020), intestinal-type carcinoma (P = .023), p53-immunopositive carcinoma (P = .007), and carcinoma with p53 mutations (P = .007).
The molecular phenotype, p27(+)Bcl-2(+)Ki-67(-)mdm2(+), was observed in 76%, 29%, and 0% of typical and atypical adenomas and carcinomas, respectively.
To elucidate the role of p53/p16(INK4a)/RB1 pathways in prostate carcinogenesis, we analyzed the p14(ARF), p16(INK4a), RB1, p21(Waf1), p27(Kip1), PTEN, p73, p53, and MDM2 gene status of multiple areas within 16 histologically heterogeneous prostate carcinomas using methylation-specific polymerase chain reaction, differential polymerase chain reaction, and immunohistochemistry.
Moreover, correlation with the status of the pRb-p53-MDM2 network showed that the cases with aberrant pRb expression displayed significantly higher E2F-1 indexes (p=0.033), while a similar association was noticed in the group of carcinomas with deregulation of the p53-MDM2 feedback loop.
We have examined here the pattern of expression of Mdm2 in a series of 192 human lung carcinomas of all histological types using both immunohistochemical and Western blot analyses and four distinct antibodies mapping different epitopes onto the Mdm2 protein.
Aberrant expression of pRb (Ab) and overexpression of p53 (P) and MDM2 (P) proteins were observed in 39%, 57%, and 68% of the carcinomas, respectively.
Fifty-three neuroendocrine lung tumors (24 carcinoids, one atypical carcinoid, five large-cell neuroendocrine carcinomas, and 23 small-cell lung carcinomas) were investigated for immunocytochemical expression of several gene products, i.e., p53, Rb, bcl-2, c-kit, mdm-2, cdk-4, p21 proteins, and proliferation index as assessed by MIB-1.
Immunohistochemical p53 status was directly correlated with mdm-2 (p = 0.0001), p21 (p = 0.0004) and inversely with bcl-2 (p = 0.005) expression. bcl-2 proved to be an independent marker of prognosis, p53 only in the group of node-positive carcinomas, whereas bcl-2-/p53+ tumours revealed the worst prognosis.
By use of immunohistochemistry, we examined the expression of p21(WAF-1/CIP-1) in 60 patients with urothelial carcinomas and compared the results with the status of nuclear p53 and mdm2 accumulation, expression of type IV collagen in the basement membranes and upregulation of metalloproteinases (MMP-1, MMP-2, MMP-9).
Recent reports have revealed that mdm2 exerts its negative regulation on the p53 signal by directly binding p53 protein and thereby instigating its proteasomal degradation. mdm2 has been shown to exist in alternatively spliced forms in human ovarian and bladder carcinomas, and recently in GBM, with loss or disruption of its p53 binding domain.
The aims of this study were to study aberrant expression and coexpression of the cell cycle associated proteins TP53, p21, p27, cyclin D1, cdk4, RB, EGFR, and MDM2 in cervical carcinomas, to correlate protein alterations with histopathological and clinical parameters, and to evaluate whether these alterations provide prognostic information.
The present study represents a continuation of previous works in which we observed that lung carcinomas co-expressing MDM2 protein and p53 mutants (mt p53) exhibited more aggressive behaviour.
An important finding of the study was that multiple impairments (three and four molecules affected) of the p16/pRb/p53/MDM2 network occurred in a large proportion (43%) of the carcinomas.