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Título: Signaling pathways implicated in p75 neurotrophin receptor-mediated neuronal survival and death
Autores: Roux, Philippe P.
Fecha: 2002
Publicador: McGill University - MCGILL
Fuente:
Tipo: Electronic Thesis or Dissertation
Tema: Biology, Molecular.
Biology, Neuroscience.
Descripción: The neurotrophins are growth factors involved in the development, maintenance, survival, and death of the nervous system. The signal transducing systems that mediate the diverse biological functions of the neurotrophins are initiated by their interactions with two categories of cell surface receptors, the Trk family of tyrosine kinases, and the p75 neurotrophin receptor (p75NTR). In contrast to the rapid progress made in elucidating the mechanism of action of the Trk receptors, the physiological roles of p75NTR are uncertain, but two general functions have been ascribed to p75NTR. First, p75NTR can positively or negatively modulate Trk receptor signaling, and second, p75NTR can autonomously activate signaling cascades that results in cellular apoptosis. The signaling pathways employed by p75NTR to mediate its effects are unclear, but p75NTR was found to activate the NF-kappaB and JNK pathways, and to interact with several adaptor proteins, such as NRAGE, NADE, NRIF, TRAF proteins, and FAP-1.
Nervous system injuries represent interesting models to study p75NTR because several types of injury induce p75NTR expression. In the first part of this thesis, we have used the pilocarpine model of seizure in the rat and found that this type of injury induces neuronal apoptosis and p75NTR expression. Apoptosis was tightly linked with p75NTR expression, suggesting that p75NTR may promote apoptosic cell death after seizure, and consistent with this, we have found that p75NTR can promote JNK activation and apoptosis in vitro. In the second study, we discovered that p75NTR can also facilitate survival under some cellular circumstances. The survival-promoting effect of p75NTR was accompanied with PI3-K-dependent Akt activation, and correlated with a reduction in cytosolic protein tyrosine phosphatase activity, suggesting that p75NTR may regulate a tyrosine phosphatase involved in the regulation of Akt and survival. In the last study, we have found that the related neuroprotective compounds, K252a and CEP 1347, are potent. MLK3 inhibitors, yet they simultaneously activated Akt and ERK, and survival through MLK3-independent mechanisms. These findings suggested that K252a and CEP1347 may act on a novel target responsible for their survival-promoting activities.
Taken together, the data in this thesis adds to our understanding of the physiological functions of p75NTR, and contributes to our knowledge of the cellular machinery that control neuronal cell survival and death.
Idioma: en