Navegando por Palavras-chave "P2 Purinergic Receptors"

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    Avaliação dos mecanismos intracelulares da diferenciação mielóide por receptores P2
    (Universidade Federal de São Paulo (UNIFESP), 2019-06-27) Araujo Junior, Roberto Theodoro De [UNIFESP]; Gamero, Edgar Julian Paredes [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Hematopoiesis is the process by which the organism forms all the bloodlines that occurs throughout the life of the individual. The capacity for self-renewal, quiescence and differentiation in multiple steps presented by hematopoietic stem cells (HTCs) are essential characteristics for the maintenance of homeostasis of hematopoietic tissue. In addition to cytokines, other signaling agents such as ATP, secreted by endothelial cells and osteoblasts, can modulate hematopoiesis by the activation of extracellular receptors. Several works have shown the capacity of ATP and analogues, in activating P2 receptors, and in modulating the activity of mature hematopoietic cells and in CTHs. Our group demonstrated that extracellular ATP promotes differentiation of HTCs through the increase of intracellular calcium promoted by P2 receptors. Although the modulation of hematopoiesis by ATP and analogs through the activation of P2 receptors has been observed, the receptor subtypes involved and the intracellular pathways that depend on these effects have not been fully elucidated. This work aims to elucidate the intracellular pathways related to the induction of myeloid differentiation promoted by P2 receptors. It was demonstrated in the present study that CTHs undergo differentiation through the activation of P2 receptors, ATP-treated HTCs increase Ki67 cell proliferation marker expression, thus indicating that these cells have lost the characteristic quiescence of HTCs. In addition, the Pi3K / AKT pathways were activated, and AKT was phosphorylated at both activation sites, thus demonstrating that both the PDK-1 enzyme and the mTOR protein complex are involved in signaling this process. CaMKII and PKC enzymes of the calcium dependent pathways were also activated, but without activation of CaMKIV. Among the pathways activated by P2Y receptors are those of PLCβ3 which, among other actions, is capable of inducing an increase in cytosolic calcium. Some transcription factors such as Stats 3 and 5 were also evaluated, both of which were activated by Janus kinase-independent pathways, as well as the best known Bcl-2 oncoprotein due to its participation in the apoptotic control process, but which has a role in the process of cell differentiation. Finally, the ERK was activated in a sustained manner for up to 24 hours, the process of activation of the ERK pathway is strongly linked to differentiation processes, and to corroborate this result a specific inhibitor for MEK was able to reverse the induced differentiation process by ATP. xviii These data together suggest that P2 receptors lead hematopoietic stem cells to differentiate themselves by signaling many pathways and that the role of MAPK ERK is of fundamental importance for this process.