The p53-homologue p63 may promote thyroid cancer progression

Abstract

Inactivation of p53 and p73 is known to promote thyroid cancer progression. We now describe p63 expression and function in human thyroid cancer. TAp63a is expressed in most thyroid cancer specimens and cell lines, but not in normal thyrocytes. However, in thyroid cancer cells TAp63a fails to induce the target genes (p21Cip1, Bax, MDM2) and, as a consequence, cell cycle arrest and apoptosis occur. Moreover, TAp63a antagonizes the effect of p53 on target genes, cell viability and foci formation, and p63 gene silencing by small interfering (si) RNA results in improved p53 activity. This unusual effect of TAp63a depends on the protein C-terminus, since TAp63b and TAp63g isoforms, which have a different arrangement of their C-terminus, are still able to induce the target genes and to exert tumour-restraining effects in thyroid cancer cells. Our data outline the existence of a complex network among p53 family members, where TAp63a may promote thyroid tumour progression by inactivating the tumour suppressor activity of p53.

TAp73α Increases p53 Tumor Suppressor Activity in Thyroid Cancer Cells via the Inhibition of Mdm2-Mediated Degradation

“…Because the SAM domain is a site module for protein-protein interaction in both p63 and p73, it is possible that thyroid cancer cells express proteins acting as TAp73a corepressors (1,14,(60)(61)(62). A similar mechanism has already been described for TAp63a able to antagonize p53 effects in thyroid cancer cells (37).…”

“…Finally, the aberrant expression of TAp63a and TAp73a isoforms may favor tumor progression and chemoresistance in some cancer cells (35)(36)(37). Taken together, these results indicate that, depending on the cell context, cooperation among p53 family members may be either synergistic or antagonistic with respect to tumor suppression.…”

“…One model of deregulated interaction among p53 family members is represented by thyroid cancer cells, which may express TAp63a, DNp73a and may harbor p53 mutations (37)(38)(39)(40)(41)(42)(43)(44)(45)(46). It is noteworthy that the ectopic expression of p53 by gene delivery in thyroid cancer cells harboring p53 mutations is not able to fully restore p53 tumor suppressor function (47)(48)(49)(50)(51).…”

Gene expression profile of human thyroid cancer in relation to its mutational status

“…Gal-3, an adhesion-related and simultaneously anti-apoptotic molecule, was upregulated in most ATCs and thyroid carcinoma cell lines harboring the most frequently detected p53 mutation, R273H. Over-expression of the p53 protein (TP53) was also found to be correlated with the upregulation of its antagonist p63, a member of the p53 protein family (Malaguarnera et al 2005) and the GLUT1 (Kim et al 2006). Schwartzenberg- Bar-Yoseph et al (2004) demonstrated that GLUT1 and GLUT4 are repressed by wildtype p53, and mutations within the DNA-binding domain of TP53 disable this interaction.…”

HMGA1 Inhibits the Function of p53 Family Members in Thyroid Cancer Cells

“…We and others have previously shown that although p53 family members are expressed in thyroid cancer cells (33)(34)(35), their tumor suppressor activity is kept latent in these malignant cells. Because HMGA proteins have been shown to associate with and modulate the activity of several nuclear factors (1,2,36), here, we have explored whether HMGA may also influence the function of p53 family members.…”