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The expression of the MDM2 gene, a p53 binding protein, in thyroid carcinogenesis
1Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.
Background:
The authors previously found p53 mutations in 24% of malignant thyroid tumors, representing a wide stating spectrum. Overexpression of MDM2, most often due to gene amplification, has been suggested to be an additional mechanism for abrogation of the p53 function. In the current study, MDM2 gene expression and amplification were examined in a randomly selected subset of these tumors to explore the possibility that wild-type p53 may be inactivated by complexing with MDM2 in specimens without p53 mutations.
Methods:
MDM2 gene expression and amplification were studied by Northern and Southern blot analysis, respectively. Twenty-two thyroid tumors were included: 16 papillary carcinomas, 1 follicular carcinoma, 3 anaplastic carcinomas, and 2 multinodular goiters (adenomatous goiters).
Results:
A two- to threefold increase in MDM2 expression in 4 of 20 thyroid carcinomas was found. It was noteworthy that all of these four samples harbored p53 mutations. The association between increased MDM2 expression and p53 mutation was statistically significant (P < 0.005). No evidence of MDM2 gene amplification or rearrangement accounting for such an increase in MDM2 expression was found.
Conclusions:
Genetic and/or environmental factors contributing to random p53 mutations also may cause increased MDM2 expression. Given the moderate increase in MDM2 expression without associated genetic alterations such as gene amplification and rearrangement, MDM2 may not play any significant role in the development and progression of thyroid carcinoma.
Insights
Increased MDM2 expression in thyroid tumors often correlates with p53 mutations, but without gene amplification, MDM2 may not significantly impact thyroid cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Previous research identified p53 mutations in 24% of malignant thyroid tumors.
- MDM2 overexpression, often from gene amplification, is a known mechanism to inhibit p53 function.
- This study investigates if wild-type p53 inactivation by MDM2 complexing occurs in thyroid tumors lacking p53 mutations.
Purpose of the Study:
- To examine MDM2 gene expression and amplification in thyroid tumors.
- To determine the relationship between MDM2 alterations and p53 status.
- To assess the role of MDM2 in thyroid carcinoma development.
Main Methods:
- Analyzed MDM2 gene expression using Northern blot.
- Studied MDM2 gene amplification via Southern blot.
- Included 22 thyroid tumors: 16 papillary, 1 follicular, 3 anaplastic carcinomas, and 2 multinodular goiters.
Main Results:
- A 2- to 3-fold increase in MDM2 expression was observed in 4 of 20 thyroid carcinomas.
- All 4 tumors with increased MDM2 expression also had p53 mutations (P < 0.005).
- No MDM2 gene amplification or rearrangement was detected as the cause for increased expression.
Conclusions:
- Factors causing p53 mutations may also influence MDM2 expression.
- The moderate increase in MDM2 expression, without genetic alterations, suggests a limited role in thyroid carcinoma.
- MDM2 may not be a significant factor in the development and progression of thyroid cancer.