INVESTIGADORES
VACCARO Maria Ines
congresos y reuniones científicas
Título:
CREB Mediates Gq-Coupled Receptor Activation of Vmp1, a Switch For Autophagy In Pancreas Biology And Diseases
Autor/es:
ROPOLO, A; VACCARO MI
Lugar:
Miami, USA
Reunión:
Congreso; IAP/APA Joint Meeting 2012; 2012
Institución organizadora:
International Association of Pancreatology and American Pancreatic Association
Resumen:
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CREB Mediates Gq-Coupled Receptor Activation of Vmp1, a Switch For
Autophagy In Pancreas Biology And Diseases
A.
Ropolo, A. Lo Re, M.I. Molejon, V. Boggio, M.I. Vaccaro
Department
of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos
Aires, Buenos Aires, Argentina
Autophagy is an evolutionarily
preserved degradation process of cytoplasmic cellular constituents, which
participates in cell homeostasis as well as in response to disease. Our
laboratory characterized VMP1 (Vacuole Membrane Protein 1) as an essential
autophagy related-protein that mediates zymophagy, the
selective degradation of altered secretory granules in acute pancreatitis. The aim of this work is to understand the regulatory
pathways that control vmp1 gene expression and autophagy in pancreatic cells.
Using a combination of luciferase assay, expression analysis, shRNA strategy
and chromatin
immunoprecipitation assay, we report
the identification of the promoter region of the human vmp1 gene and the
molecular pathways that lead to its activation. Here, we present the essential
sequence required for this activation containing the TATA Box and several
consensus binding sites for the transcription factors related to cellular
stress. We show that Vmp1 promoter is activated by the hyperstimulation of Gq-coupled receptors using cerulein in AR42J cells. Besides, the transfection of these cells with a Gq
constitutive activates protein induces VMP1 expression and activates the Vmp1
promoter. CREB, an effector of this axis, regulates the expression and promoter
activity of VMP1 and chromatin immunoprecipitation assays demonstrated that CREB
binds to VMP1 promoter. Moreover, we showed that the histone acetyltransferase
p300 cooperates with CREB in VMP1 promoter regulation. Conversely, RNAi
knockdown of p300 impairs CREB induced activation of this promoter. We demonstrate a transcriptional target of the Gq-coupled
receptor signaling axis in pancreatic acinar
cells.
Together these data provide evidence of a new regulatory mechanism modulating
autophagy and positions VMP1 as a switch for
autophagy in pancreas biology and diseases.