Relationship of TP53 gene with retroelements in urogenital organs carcinogenesis

Abstract

The article presents a hypothesis about the influence of TP53 gene on the development of prostate, kidney, and bladder cancer through negative regulation of retrotransposons. The p53 protein is a transcription factor that controls the expression of various protein-coding genes. The promoter regions of endogenous retroviruses contain almost ideal binding sites for p53, which suppresses translation of these elements and LINE1s. The TP53 gene contains retrotransposons, which promote mutations due to recombinations. Germinal mutations of the TP53 gene in Li–Fraumeni syndrome cause a deficiency of the p53 protein, which leads to the activation of retroelements, which, in turn, cause loss of heterozygosity of the second TP53 allele. The result is a “vicious circle” that stimulates genomic instability and carcinogenesis. This mechanism is possible for sporadic urogenital system malignant neoplasms development, where TP53 mutations are most often identified, acting as drivers of carcinogenesis. At the same time, pathological activation of retroelements is found in many malignant neoplasms. Moreover, the “vicious circle”, when a deficiency of an oncosuppressor causes activation of retroelements that contribute to inactivation of other oncosuppressors, is characteristic not only for р53. Retroelements can be controlled by other oncosuppressor genes that contain hot spots of insertional mutagenesis and retrotransposons (which contribute to recombination events). I suppose that pathological interregulation of retroelements and tumor suppressors is a universal mechanism of carcinogenesis in the development of sporadic malignant neoplasms and hereditary tumor syndromes. Chromoplexy observed in 90 % of prostate cancer samples may reflect these events, since activated retroelements in carcinogenesis contribute to complex chromosomal rearrangements.