p53 family proteins in thyroid cancer

Abstract

At variance with other human malignancies, p53 mutations are not frequent in thyroid cancer and are believed to be responsible mainly for cancer progression to poorly differentiated and aggressive phenotype. p63 and p73, two proteins with a high degree of homology with p53, are overexpressed in thyroid cancer, but their role in cancer initiation or progression is controversial. Regulation of p53 family protein function depends on: (1) the balance between the expression of transcriptionally active (p53, TAp63, and TAp73) and inactive isoforms (DNp63 and DNp73); (2) their interaction and competition at DNA-responsive elements; (3) their interaction with regulatory proteins, either inhibitory or activating. In thyroid cancer, therefore, although mutations of the p53 oncosuppressor protein family are rare, other mechanisms are present, including aberrant expression of p53 family dominant negative isoforms, up-regulation of inhibitory proteins, and functional inhibition of activating proteins. The overall result is a defective oncosuppressor activity. These inactivating mechanisms may be present in the early stages of thyroid cancer and in different cancer histotypes. A better understanding of this complex network may not only ameliorate our comprehension of cancer biology, but also open the possibility of innovative diagnostic procedures and the development of targeted therapies.

Attenuating the p53 Pathway in Human Cancers: Many Means to the Same End

“…5D) (Grasso et al 2012). There is additional evidence to suggest that p53 mutations arise late in the pathogenesis of thyroid tumors, occurring more frequently in poorly differentiated and anaplastic tumors (Shahedian et al 2001;Malaguarnera et al 2007). These examples clearly illustrate the value of comparing the genomic landscape of early primary lesions to that of late-stage and metastatic tumors to better understand the events that are essential for initiation and those that contribute to tumor progression.…”

Transcription Factors Sp1 and p73 Control the Expression of the Proapoptotic Protein NOXA in the Response of Testicular Embryonal Carcinoma Cells to Cisplatin

“…line with this, it has been proposed that regulation of p53 family protein activity depends on the relative expression of transcriptionally active proteins and inactive isoforms (42). An alternative explanation may reside in clonal differences in the expression of genes that could promote some degree of spontaneous differentiation (43), as short-term differentiation of NTERA2 cells causes a loss in p53-dependent hypersensitivity (21).…”

Identification of Polo-like Kinase 1 as a Potential Therapeutic Target in Anaplastic Thyroid Carcinoma

“…Conversely, p53 mutations are rarely seen in welldifferentiated lesions (<10%), whereas they occur in 67% to 88% of ATC (4,5). Other mechanisms, besides gene mutation, may functionally impair p53 in ATC (11,12).…”