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Inactivation of p53 gene in human and murine osteosarcoma cells
N Chandar1, B Billig, J McMaster
1Orthopaedic Research Laboratory, Allegheny-Singer Research Institute, Pittsburgh, Pennsylvania 15212.
Abstract:
We examined structure and expression of the p53 and Rb genes in a C3HOS transplantable mouse model of osteosarcoma. The results were compared to analogous studies conducted with five human osteosarcoma cell lines. The p53 gene was found rearranged in the mouse tumour. The rearrangement mapped to the first intron region of the p53 gene and as a result, no p53 expression could be detected in C3HOS tumours. Using p53 genomic probes, we have detected the same rearrangement in the original radiation-induced tumour and the various clones that were isolated from it. Deletion and rearrangement of the p53 gene were also found in three out of five of the human osteosarcoma cell lines (MG-63, G-292, Saos-2). No p53 expression could be detected in these three cell lines. In the affected human osteosarcoma cell lines, the rearrangement involved the first intron region. In addition, the mouse tumor was analysed for structural and expression changes in the Rb and the c-myc genes. Normal expression of both genes were detected in the murine tumour. Only one (Saos-2) human osteosarcoma cell line exhibited gross structural alteration in the retinoblastoma gene. The results suggest that the inactivation of p53 may be an important step in the development of osteosarcomas, and that a rearrangement affecting the first intron is common in osteosarcomas.
Insights
Rearrangement of the p53 gene, particularly in its first intron, was observed in both mouse and human osteosarcoma models. This genetic alteration leads to a lack of p53 expression, suggesting its critical role in osteosarcoma development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Osteosarcoma is a primary bone cancer with complex genetic underpinnings.
- The p53 and retinoblastoma (Rb) tumor suppressor genes are frequently implicated in cancer development.
Purpose of the Study:
- To investigate the structural and expression status of p53 and Rb genes in a mouse model of osteosarcoma.
- To compare these findings with human osteosarcoma cell lines.
Main Methods:
- Analysis of p53 and Rb gene structure and expression in a C3HOS mouse osteosarcoma model.
- Comparative analysis using five human osteosarcoma cell lines (MG-63, G-292, Saos-2).
- Utilized p53 genomic probes for rearrangement detection.
Main Results:
- The p53 gene was rearranged in the mouse osteosarcoma, specifically in the first intron, resulting in undetectable p53 expression.
- Similar p53 gene rearrangements involving the first intron were found in three of five human osteosarcoma cell lines, also leading to absent p53 expression.
- The mouse tumor showed normal expression of Rb and c-myc genes.
- One human cell line (Saos-2) displayed gross structural alteration in the Rb gene.
Conclusions:
- Inactivation of the p53 gene, through rearrangement in the first intron, appears to be a significant event in osteosarcoma development.
- First intron rearrangement of p53 is a common finding in both murine and human osteosarcomas.