RESUMO
In patients with medullary thyroid carcinoma (MTC) and type 2A multiple endocrine neoplasia (MEN2A), mutations of cysteine residues in the extracellular juxtamembrane region of the RET receptor tyrosine kinase cause the formation of covalent receptor dimers linked by intermolecular disulfide bonds between unpaired cysteines, followed by oncogenic activation of the RET kinase. The close proximity to the plasma membrane of the affected cysteine residues prompted us to investigate the possible role of the transmembrane (TM) domain of RET (RET-TM) in receptor-receptor interactions underlying dimer formation. Strong self-association of the RET-TM was observed in a biological membrane. Mutagenesis studies indicated the involvement of the evolutionary conserved residues Ser-649 and Ser-653 in RET-TM oligomerization. Unexpectedly, RET-TM interactions were also abrogated in the A639G/A641R double mutant, first identified in a sporadic case of MTC. In agreement with this, no transforming activity could be detected in full-length RET carrying the A639G and A641R mutations, which remained fully responsive to glial cell-line-derived neurotrophic factor (GDNF) stimulation. When introduced in the context of C634R - a cysteine replacement that is prevalent in MEN2A cases - the A639G/A641R mutations significantly reduced dimer formation and transforming activity in this otherwise highly oncogenic RET variant. These data suggest that a strong propensity to self-association in the RET-TM underlies - and may be required for - dimer formation and oncogenic activation of juxtamembrane cysteine mutants of RET, and explains the close proximity to the plasma membrane of cysteine residues implicated in MEN2A and MTC syndromes.
Assuntos
Membrana Celular/metabolismo , Proteínas de Drosophila/metabolismo , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Alanina/genética , Alanina/metabolismo , Sequência de Aminoácidos , Animais , Cisteína/genética , Cisteína/metabolismo , Dimerização , Dissulfetos/metabolismo , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Drosophila melanogaster , Expressão Gênica/efeitos dos fármacos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Humanos , Dados de Sequência Molecular , Mutação/genética , Ligação Proteica , Proteínas Proto-Oncogênicas c-ret/química , Proteínas Proto-Oncogênicas c-ret/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Neoplasias da Glândula Tireoide/genéticaRESUMO
A major problem in reconstructive and plastic surgery of the face is the assessment of exact distances between certain points of reference across facial contours. Incorrect estimation of these variables produces unsatisfactory postoperative anatomical results. Therefore a method, which permits exact measurements using stereoscopic photography of models, was tested. On the models quantitative studies of the effects of surgical techniques were made. Facial asymmetry and various phases of facial animation can be assessed and documented, and the progress of expanding tumours can likewise be followed.
Assuntos
Cefalometria/métodos , Face/cirurgia , Cirurgia Plástica/métodos , Adulto , Assimetria Facial , Feminino , Humanos , FotogrametriaRESUMO
We tried to implanted permanent magnets in the eye lid to cure lagophthalmos. But severe complications occurred very often, mainly decubitus with expulsion of the magnet through the skin. We think that it is necessary to change the system to get better results with permanent magnets in the treatment of lagophthalmos.