Trans-regulated silencing and reactivation of TP53 tumor suppressor gene in malignant transformation and its reversion.

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.