Phosphorylation of the translation initiation factor eIF-2alpha has been shown to be a major mechanism controlling protein synthesis in eukaryotic cells, yet the developmental and physiological consequences of this regulation are largely unknown in whole organisms. By using the diverse tools of Drosophila genetics we propose to critically test the functional importance of eIF-2alpha phosphorylation and, in addition, investigate the function of an eIF-2alpha kinase, GCN2. In lower eukaryotes, GCN2 senses amino acid deprivation and through the general control pathway derepresses amino acid biosynthesic genes. In higher eukaryotes the function of GCN2 is unknown but likely to be more complex by virtue of its expression in the developing and mature central nervous system and because the response to amino acid deprivation in higher eukaryotes is dependent upon whether essential or non- essential amino acids are limiting. The most important objective of this proposal is the isolation of loss of function mutations of eIF-2alpha and GCN2. Loss of function mutations are likely to give us immediate clues as to developmental functions and these mutations will be form the basis of several of the other specific aims. Other experiments are proposed to identify downstream targets of GCN2 and specific developmental and physiological processes impacted by the control of translation initiation as mediated by the phosphorylation of eIF-2alpha.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056957-02
Application #
6138619
Study Section
Genetics Study Section (GEN)
Program Officer
Anderson, James J
Project Start
1999-01-01
Project End
2000-08-31
Budget Start
2000-01-01
Budget End
2000-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$149,506
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Xu, Xu; Gupta, Sounak; Hu, Wenli et al. (2011) Hyperthermia induces the ER stress pathway. PLoS One 6:e23740
Gupta, Sounak; McGrath, Barbara; Cavener, Douglas R (2010) PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway. Diabetes 59:1937-47
Feng, Daorong; Wei, Jianwen; Gupta, Sounak et al. (2009) Acute ablation of PERK results in ER dysfunctions followed by reduced insulin secretion and cell proliferation. BMC Cell Biol 10:61
Gupta, Sounak; McGrath, Barbara; Cavener, Douglas R (2009) PERK regulates the proliferation and development of insulin-secreting beta-cell tumors in the endocrine pancreas of mice. PLoS One 4:e8008
Iida, Kaori; Li, Yulin; McGrath, Barbara C et al. (2007) PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice. BMC Cell Biol 8:38
Guo, Feifan; Cavener, Douglas R (2007) The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab 5:103-14
Zhang, Wei; Feng, Daorong; Li, Yulin et al. (2006) PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab 4:491-7
Owen, Cheri R; Kumar, Rita; Zhang, Peichuan et al. (2005) PERK is responsible for the increased phosphorylation of eIF2alpha and the severe inhibition of protein synthesis after transient global brain ischemia. J Neurochem 94:1235-42
Jiang, Hao-Yuan; Wek, Sheree A; McGrath, Barbara C et al. (2004) Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol Cell Biol 24:1365-77
Li, Yulin; Iida, Kaori; O'Neil, Jeff et al. (2003) PERK eIF2alpha kinase regulates neonatal growth by controlling the expression of circulating insulin-like growth factor-I derived from the liver. Endocrinology 144:3505-13

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