No evidence for functional inactivation of wild-type p53 protein by MDM2 overexpression in gastric carcinogenesis.
Inactivation of wild-type p53 during gastric carcinogenesis is usually caused by mutations within exons 5-8 of the p53 gene leading to mutated, usually immunohistochemically detectable p53 proteins. However, functional inactivation of wild-type p53, mimicking mutational inactivation, may also result from binding to overexpressed MDM2 protein. While these two mechanisms of p53 inactivation are considered to be mutually exclusive, no data exist as to whether MDM2 overexpression occurs during gastric carcinogenesis. MDM2 protein overexpression was therefore studied in relation to p53 protein accumulation in gastric carcinogenesis. Forty-five paraffin-embedded gastrectomy specimens from early gastric carcinomas were examined for the presence of chronic active gastritis, chronic atrophic gastritis, subtypes of intestinal metaplasia, and dysplasia. The Lauren type was reassessed for all early carcinomas. p53 protein accumulation was examined using the monoclonal antibody DO-7. MDM2 protein overexpression was assessed with the monoclonal antibody SMP-14. Complete absence of nuclear p53 protein accumulation was observed in chronic active gastritis, chronic atrophic gastritis, and intestinal metaplasia, irrespective of the subtype. In gastric dysplasia (one mild, two moderate, one severe), only severe dysplasia was p53-positive. Intestinal-type (n = 20) and diffuse-type early gastric carcinoma (n = 25) were p53-positive in 70 and 52 per cent of the cases, respectively. MDM2 protein overexpression was not observed during gastric carcinogenesis, either in the p53-positive or in the p53-negative cases. In conclusion, it appears that functional inactivation of wild-type p53 by MDM2 protein overexpression plays no role in (early) gastric carcinogenesis.
Blok
P
P
Department of Pathology, Westeinde Ziekenhuis, The Hague, The Netherlands. blok@westeinde.ziekenhuis.nl
Craanen
M E
ME
Dekker
W
W
Offerhaus
G J
GJ
Tytgat
G N
GN
D002908:Chronic Disease; D005756:Gastritis / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins; D011230:Precancerous Conditions / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D013274:Stomach Neoplasms / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2