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Trans-regulated silencing and reactivation of TP53 tumor suppressor gene in malignant transformation and its
1Radiation Biology Center, Kyoto University, Yoshida-Konoecho, Sakyo-ku, Kyoto 606-8501, Japan.
Abstract:
Despite growing interest in the methylation-mediated silencing of tumor suppressor genes in the neoplastic process, its signaling mechanism remains largely unknown. Here we show in a cultured murine cell line system that the silencing and reactivation of tumor suppressor gene TP53 were reversibly controlled by a trans-acting regulatory mechanism. The gene product p53, which was constitutively expressed and activated upon X-ray irradiation in non-malignant parental cell line, was undetectable in its X-ray-induced malignant transformants, while they retained a wild-type TP53. The silencing was cancelled by transferring a human chromosome 11 and the expression of p53 was restored. The non-malignant revertants thus obtained were again susceptible to transformation by X-irradiation, giving rise to re-transformants, in which p53 was again repressed while the human chromosome 11 retained the ability to turn on TP53 when it was transferred into other malignant clone. The silent TP53 could be reactivated by treatment with the demethylating agent 5-azadeoxycytidine. These observations indicate the presence of a trans-acting signaling mechanism in the methylation-mediated regulation of TP53 expression which is associated with the acquisition of malignancy.
Insights
Tumor suppressor gene TP53 silencing in cancer is reversible, controlled by a trans-acting mechanism. Reactivation of TP53 expression was observed via chromosome transfer and demethylating agents, indicating a signaling pathway in malignancy.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Methylation-mediated silencing of tumor suppressor genes is implicated in cancer, but the underlying signaling mechanisms are poorly understood.
- The tumor suppressor gene TP53 plays a critical role in preventing cancer, and its dysregulation is common in neoplastic processes.
Purpose of the Study:
- To investigate the signaling mechanism controlling the methylation-mediated silencing and reactivation of the tumor suppressor gene TP53.
- To determine the role of trans-acting factors in TP53 regulation during neoplastic transformation.
Main Methods:
- Utilized a cultured murine cell line system to study TP53 gene expression.
- Employed X-ray irradiation to induce malignant transformation and observed changes in p53 protein levels.
- Investigated the effect of human chromosome 11 transfer on TP53 expression.
- Assessed the impact of the demethylating agent 5-azadeoxycytidine on TP53 reactivation.
Main Results:
- TP53 expression, normally induced by X-ray irradiation in non-malignant cells, was undetectable in X-ray-induced malignant transformants retaining wild-type TP53.
- Transferring a human chromosome 11 restored p53 expression in malignant cells, and these revertants became susceptible to further transformation.
- The silent TP53 in malignant cells could be reactivated by treatment with 5-azadeoxycytidine.
- The human chromosome 11 consistently restored TP53 expression when transferred into different malignant clones.
Conclusions:
- A trans-acting regulatory mechanism controls the reversible silencing and reactivation of TP53 expression.
- Methylation-mediated regulation of TP53 is associated with the acquisition of malignancy.
- These findings elucidate a novel signaling pathway involved in tumor suppressor gene regulation and cancer development.
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