title: H4(D10S170), a gene frequently rearranged with RET in papillary thyroid carcinomas: functional characterization.
abstract: Human thyroid papillary carcinomas are characterized by rearrangements of the RET protooncogene with a number of heterologous genes, which generate the RET/papillary thyroid carcinoma (PTC) oncogenes. One of the most frequent variants of these recombination events is the fusion of the intracellular kinase-encoding domain of RET to the first 101 amino acids of a gene named H4(D10S170). We have characterized the H4(D10S170) gene product, showing that it is a ubiquitously expressed 55 KDa nuclear and cytosolic protein that is phosphorylated following serum stimulation. This phosphorylation was found to depend on mitogen-activated protein kinase (MAPK) Erk1/2 activity and to be associated to the relocation of H4(D10S170) from the nucleus to the cytosol. Overexpression of the H4(D10S170) gene was able to induce apoptosis of thyroid follicular epithelial cells; conversely a carboxy-terminal truncated H4(D10S170) mutant H4(1-101), corresponding to the portion included in the RET/PTC1 oncoprotein, behaved as dominant negative on the proapoptotic function and nuclear localization of H4(D10S170). Furthermore, conditional expression of the H4(D10S170)-dominant negative truncated mutant protected cells from stress-induced apoptosis. The substitution of serine 244 with alanine abrogated the apoptotic function of H4(D10S170). These data suggest that loss of the H4(D10S170) gene function might have a role in thyroid carcinogenesis by impairing apoptosis.
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o, University Federico II, Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Celetti
authors.forename: Aniello
authors.initials: A
authors.lastname: Cerrato
authors.forename: Francesco
authors.initials: F
authors.lastname: Merolla
authors.forename: Donata
authors.initials: D
authors.lastname: Vitagliano
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Vecchio
authors.forename: Michele
authors.initials: M
authors.lastname: Grieco
mesh_terms: D000818:Animals; D017209:Apoptosis; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D015321:Gene Rearrangement; D006801:Humans; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D011817:Rabbits; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C494999:Ret protein, mouse; C093573:ret-PTC fusion oncoproteins, human; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases