Study of the role of GCN1 in the genesis of metabolic diseases in mice
Translational regulation mediated by GCN2: modulation by the actin cytoskeleton
Grant number: | 09/52047-5 |
Support Opportunities: | Research Projects - Thematic Grants |
Field of knowledge: | Biological Sciences - Biochemistry - Molecular Biology |
Principal Investigator: | Beatriz Amaral de Castilho |
Grantee: | Beatriz Amaral de Castilho |
Host Institution: | Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil |
Associated research grant(s): | 14/23889-6 - GCN1 and its interactor Yih1/IMPACT: their function in and beyond translational control,
AV.EXT 13/50377-3 - Alternative translation mechanisms in health and disease, AP.R |
Associated scholarship(s): | 14/17145-4 - Translational regulation mediated by GCN2: modulation by the actin cytoskeleton,
BP.PD 14/07850-2 - Relevance of IMPACT protein in metabolism regulation, BP.IC |
Abstract
Translational control mediated by the phosphorylation of eukaryotic initiation factor -2 (eIF2) is important for cellular adaptation to a variety of environmental stress situtations, and its impairment results in pathological conditions in humans. One elF2 kinase, GCN2, extensively studied in the yeast model, has recently been the focus of major findings in mammalian physiology. GCN2 controls protein synthesis and the induction of a complex gene regulatory network in response to e.g., amino acid starvation. The study of mice devoid of GCN2 revealed that this protein kinase plays a role managing starvation for nutrients and determining feeding behavior and memory. Our previous work showed that the mammalian protein IMPACT is an inhibitor of GCN2. IMPACT binds to GCN1, an effectors of GCN2. Interestingly, IMPACT is predominantly expressed in neurons. This project addresses the mechanisms by which IMPACT and GCN1 modulate GCN2 activity in neurons and explores the consequences of the lack of IMPACT in mammalian physiology. Other potential functions of IMPACT and GCN1 will be addressed. The elF2 signaling pathway also directs differentiation processes in pathogenic organisms. We have previously shown that trypanosomatids contain an unusual form of elF2, and three elF2 kinases that may function as sensors of the different environmental conditions encountered by the parasites during their life cycle. This project will also dissect the role of the elF2 signaling pathway in trypanosomes. Together, the project aims are important for understanding the molecular mechanisms evolved by eukaryotic organisms to adapt a highly conserved translational regulatory module to maintain homeostasis or to promote differentiation. (AU)
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