Browsing by Author "Urra, Soledad"

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    Differential expression profile of CXCR3 splicing variants is associated with thyroid neoplasia. Potential role in papillary thyroid carcinoma oncogenesis?
    (2018) Urra, Soledad; Fischer, Martin C.; Martinez, Jose R.; Veliz, Loreto; Orellana, Paulina; Solar González, Antonieta Alejandra; Bohmwald Prieto, Karen; Kalergis Parra, Alexis Mikes; Riedel, Claudia; Corvalán R., Alejandro; Roa Strauch, Juan Carlos Enrique; Fuentealba, Rodrigo; Cáceres, C. Joaquín; López Lastra, Marcelo Andrés; León Ramírez, Augusto; Droppelmann, Nicolás; Gonzalez, Hernan E.
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    Genetic testing for indeterminate thyroid cytology: review and meta-analysis.
    (2018) Vargas Salas, Sergio; Martinez, Jose R.; Urra, Soledad; Domínguez Ruiz-Tagle, José Miguel; Mena, Natalia; Uslar, Thomas; Lagos Lucero, Marcela; Henríquez Henríquez, Marcela Patricia; González Díaz, Hernán
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    p75 Neurotrophin Receptor-mediated Apoptosis in Sympathetic Neurons Involves a Biphasic Activation of JNK and Up-regulation of Tumor Necrosis Factor-α-converting Enzyme/ADAM17
    (2010) Kenchappa, Rajappa S.; Tep, Chhavy; Korade, Zeljka; Urra, Soledad; Bronfman, Francisca C.; Yoon, Sung Ok; Carter, Bruce D.
    During the development of the sympathetic nervous system, the p75 neurotrophin receptor (p75NTR) has a dual function: promoting survival together with TrkA in response to NGF, but inducing cell death upon binding pro or mature brain-derived neurotrophic factor (BDNF). Apoptotic signaling through p75NTR requires activation of the stress kinase, JNK. However, the receptor also undergoes regulated proteolysis, first by a metalloprotease, and then by gamma-secretase, in response to pro-apoptotic ligands and this is necessary for receptor mediated neuronal death (Kenchappa, R. S., Zampieri, N., Chao, M. V., Barker, P. A., Teng, H. K., Hempstead, B. L., and Carter, B. D. (2006) Neuron 50, 219-232). Hence, the relationship between JNK activation and receptor proteolysis remains to be defined. Here, we report that JNK3 activation is necessary for p75NTR cleavage; however, following release of the intracellular domain, there is a secondary activation of JNK3 that is cleavage dependent. Receptor proteolysis and apoptosis were prevented in sympathetic neurons from jnk3(-/-) mice, while activation of JNK by ectopic expression of MEKK1 induced p75NTR cleavage and cell death. Proteolysis of the receptor was not detected until 6 h after BDNF treatment, suggesting that JNK3 promotes cleavage through a transcriptional mechanism. In support of this hypothesis, BDNF up-regulated tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM17 mRNA and protein in wildtype, but not jnk3(-/-) sympathetic neurons. Down-regulation of TACE by RNA interference blocked BDNF-induced p75NTR cleavage and apoptosis, indicating that this metalloprotease is responsible for the initial processing of the receptor. Together, these results demonstrate that p75NTR-mediated activation of JNK3 is required for up-regulation of TACE, which promotes receptor proteolysis, leading to prolonged activation of JNK3 and subsequent apoptosis in sympathetic neurons.
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    TrkA receptor activation by nerve growth factor induces shedding of the p75 neurotrophin receptor followed by endosomal gamma-secretase-mediated release of the p75 intracellular domain
    (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2007) Urra, Soledad; Escudero, Claudia A.; Ramos, Patricio; Lisbona, Fernanda; Allende, Edgardo; Covarrubias, Paulina; Parraguez, Jose I.; Zampieri, Niccolo; Chao, Moses V.; Annaert, Wim; Bronfman, Francisca C.
    Neurotrophins are trophic factors that regulate important neuronal functions. They bind two unrelated receptors, the Trk family of receptor-tyrosine kinases and the p75 neurotrophin receptor (p75). p75 was recently identified as a new substrate for gamma-secretase-mediated intramembrane proteolysis, generating a p75-derived intracellular domain (p75-ICD) with signaling capabilities. Using PC12 cells as a model, we studied how neurotrophins activate p75 processing and where these events occur in the cell. We demonstrate that activation of the TrkA receptor upon binding of nerve growth factor (NGF) regulates the metalloprotease-mediated shedding of p75 leaving a membrane-bound p75 C-terminal fragment (p75-CTF). Using subcellular fractionation to isolate a highly purified endosomal fraction, we demonstrate that p75-CTF ends up in endosomes where gamma-secretase-mediated p75-CTF cleavage occurs, resulting in the release of a p75-ICD. Moreover, we show similar structural requirements for gamma-secretase processing of p75 and amyloid precursor protein-derived CTFs. Thus, NGF-induced endocytosis regulates both signaling and proteolytic processing of p75.