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Short alternative splice transcripts of the mdm2 oncogene correlate to malignancy in human astrocytic neoplasms
R Matsumoto1, M Tada, M Nozaki
1Laboratory for Molecular Brain Research, Hokkaido University School of Medicine, Sapporo, Japan.
Abstract:
The mdm2 oncogene encodes a 90-kDa nuclear phosphoprotein that binds and inhibits the function of the p53 tumor suppressor protein. It was recently reported that the expression of alternatively spliced variants of mdm2 correlated with malignancy in ovarian tumors and bladder carcinomas. We analyzed the presence of alternatively spliced mdm2 variants and studied their correlation to p53 status in a total of 66 human astrocytic tumors, including 32 glioblastomas multiforme, 17 anaplastic astrocytomas, 12 astrocytomas, and 5 pilocytic astrocytomas, using a specific nested reverse transcription-PCR technique. The full-length mdm2 transcript was demonstrated in all of the cases. Multiple-sized PCR products were found in 29 cases. Two of 5 pilocytic astrocytomas (40%), none of 12 astrocytomas, and 5 of 17 anaplastic astrocytomas (29%) showed alternative splice variants. In contrast, 22 of 32 glioblastomas (69%) showed the presence of splice variants, demonstrating a significantly higher frequency than in lower-grade astrocytomas (P < 0.0003). A majority of the splice variants were 707 base-type (mdm2-b), which was confirmed by sequence analysis. There was no apparent correlation of the presence of mdm2 splice variants with p53 gene status. These results suggest a new role for mdm2, independent of p53 gene status, as an oncogene in the development of malignant astrocytic tumors.
Insights
Alternative splice variants of the mdm2 oncogene are frequently found in malignant astrocytic tumors, suggesting a role independent of p53 tumor suppressor protein status.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The mdm2 oncogene encodes a protein that inhibits the p53 tumor suppressor.
- Alternative splicing of mdm2 has been linked to malignancy in other cancers.
- The role of mdm2 splice variants in astrocytic tumors is not well understood.
Purpose of the Study:
- To investigate the presence of alternatively spliced mdm2 variants in human astrocytic tumors.
- To correlate mdm2 splice variants with tumor grade and p53 status.
Main Methods:
- Nested reverse transcription-PCR was used to analyze mdm2 splice variants in 66 astrocytic tumors.
- Tumor samples included glioblastoma multiforme, anaplastic astrocytoma, astrocytoma, and pilocytic astrocytoma.
- Sequence analysis confirmed the identity of splice variants.
Main Results:
- Full-length mdm2 transcript was present in all tumors.
- Alternative splice variants were detected in 40% of pilocytic astrocytomas, 29% of anaplastic astrocytomas, and 69% of glioblastoma multiforme.
- The frequency of splice variants was significantly higher in glioblastomas compared to lower-grade astrocytomas (P < 0.0003).
- The mdm2-b variant was the most common splice variant.
- No correlation was found between mdm2 splice variants and p53 gene status.
Conclusions:
- Alternatively spliced mdm2 variants are prevalent in malignant astrocytic tumors, particularly glioblastomas.
- The presence of these variants suggests a potential oncogenic role for mdm2 in astrocytoma development, independent of p53.
- Further research is warranted to explore the specific functions of mdm2 splice variants in gliomagenesis.