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Mutations in the Extracellular Domain Cause RET Loss of Function by a Dominant Negative Mechanism

Cosma, Maria Pia; Cardone, Monica; Carlomagno, Francesca; Colantuoni, Vittorio
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /06/1998 EN
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16.54%
The RET proto-oncogene encodes a tyrosine kinase receptor expressed in neuroectoderm-derived cells. Mutations in specific regions of the gene are responsible for the tumor syndromes multiple endocrine neoplasia types 2A and 2B (MEN 2A and 2B), while mutations along the entire gene are involved in a developmental disorder of the gastrointestinal tract, Hirschsprung’s disease (HSCR disease). Two mutants in the extracellular domain of RET, one associated with HSCR disease and one carrying a flag epitope, were analyzed to investigate the impact of the mutations on RET function. Both mutants were impeded in their maturation, resulting in the lack of the 170-kDa mature form and the accumulation of the 150-kDa immature form in the endoplasmic reticulum. Although not exposed on the cell surface, the 150-kDa species formed dimers and aggregates; this was more pronounced in a double mutant bearing a MEN 2A mutation. Tyrosine phosphorylation and the transactivation potential were drastically reduced in single and double mutants. Finally, in cotransfection experiments both mutants exerted a dominant negative effect over protoRET and RET2A through the formation of a heteromeric complex that prevents their maturation and function. These results suggest that HSCR mutations in the extracellular region cause RET loss of function through a dominant negative mechanism.

Asymmetrical Distribution of Neisseria Miniature Insertion Sequence DNA Repeats among Pathogenic and Nonpathogenic Neisseria Strains

De Gregorio, Eliana; Abrescia, Chiara; Carlomagno, M. Stella; Di Nocera, Pier Paolo
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /07/2003 EN
Relevância na Pesquisa
16.54%
Neisseria miniature insertion sequences (nemis) are miniature DNA insertion sequences found in Neisseria species. Out of 57 elements closely flanking cellular genes analyzed by PCR, most were conserved in Neisseria meningitidis but not in N. lactamica strains. Since mRNAs spanning nemis are processed by RNase III at hairpins formed by element termini, gene sets could selectively be regulated in meningococci at the posttranscriptional level.