p73 tumor-suppressor activity is impaired in human thyroid cancer.
The p73 protein is a member of the p53 family and, like p53, can induce cell-cycle arrest and apoptosis in response to DNA damage. Because the loss of p53 function is responsible for the progression of well-differentiated thyroid cancer to more aggressive phenotypes, we hypothesized that p73 might also be involved in thyroid carcinogenesis. We find that normal thyrocites do not express p73, whereas most thyroid malignancies are positive for p73 expression. However, the p73 protein of thyroid cancer cells is unresponsive to DNA-damaging agents, failing to elicit a block of the cell cycle or an apoptotic response. Notably, overexpression of transcriptionally active p73 in thyroid cancer lines can arrest the cell cycle but is still unable to induce cell death. The loss of p73 biological activity in neoplastic thyroid cells is partly explained by its interaction with transcriptionally inactive variants of p73 (DeltaNp73) and with mutant p53. Our findings suggest that the functional impairment of p73 could be involved in the development of thyroid malignancies, defining p73 as a potential therapeutic target for thyroid cancer.
Frasca
Francesco
F
Dipartimento di Medicina Interna e di Medicina Specialistica - Endocrinologia, Università di Catania, 95123 Catania.
Vella
Veronica
V
Aloisi
Alessandra
A
Mandarino
Angelo
A
Mazzon
Emanuela
E
Vigneri
Riccardo
R
Vigneri
Paolo
P
D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human