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Ha-ras interference with thyroid cell differentiation is associated with a down-regulation of thyroid transcription factor-1 phosphorylation

AuthorsVelasco, Juan A.; Acebrón, Alvaro; Zannini, Mariastella; Martín-Pérez, Jorge CSIC ORCID ; Lauro, Roberto di; Santisteban, Pilar CSIC ORCID
Issue DateJun-1998
PublisherEndocrine Society
CitationEndocrinology 139(6): 2796-2802 (1998)
AbstractMechanisms responsible for the lack of thyroid-specific differentiation markers in Ha-ras transformed FRTL-5 cells have been investigated. In vivo cell labeling and immunoprecipitation demonstrate that phosphorylation of the thyroid transcription factor-1 (TTF-1) is clearly reduced in thyroid cells transformed with the Ha-ras oncogene. Fingerprinting analysis of phosphotryptic peptides from FRTL-5 and Ha-ras-FRTL-5 cells also reveals a heterogeneous pattern of TTF-1 phosphorylation in the transformed cell line. This heterogeneity is localized in the amino terminal cluster of phosphoserines, as determined by transfection of HeLa cells with TTF-1 mutants in which serine residues have been replaced by alanines. Amplification and nucleotide sequence of the 5'-coding region of the TTF-1 gene in Ha-ras-FRTL-5 cells rule out the possibility that differences in phosphorylation were the consequence of any mutational event affecting residues within the N-terminal protein sequence. Hypophosphorylated TTF-1 is still able to bind its DNA consensus sequence within the thyroglobulin promoter, although a reporter construct whose expression is exclusively dependent on TTF-1 is not transactivated. Transfection of Ha-ras-FRTL-5 cells with an expression vector encoding the cAMP dependent protein kinase A (PKA) catalytic subunit partially reestablishes TTF-1 transcriptional activity. Taken together, these results indicate that the lack of specific thyroid gene expression in Ha-ras-FRTL-5 cells could be a direct consequence of the inability of TTF-1 to promote transcription.
Description7 pages, 6 figures.
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Appears in Collections:(IIBM) Artículos

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