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Role of GCN2 in guiding the cellular and molecular response to asparaginase in the pancreas
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Phillipson-Weiner, Lindsey. Role of GCN2 in guiding the cellular and molecular response to asparaginase in the pancreas. Retrieved from https://doi.org/doi:10.7282/T3M90BNF

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TitleRole of GCN2 in guiding the cellular and molecular response to asparaginase in the pancreas
NamePhillipson-Weiner, Lindsey (author); Anthony, Tracy G (chair); Watford, Malcolm (internal member); McAuliffe, Geoffrey (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2015
Other Date2015-10 (degree)
SubjectNutritional Sciences, Asparaginase, Pancreatitis
Extent1 online resource (xiii, 78 p. : ill.)
DescriptionAsparaginase is a chemotherapy agent used in the treatment of acute lymphoblastic leukemia. Asparaginase can cause severe pancreatitis but the molecular basis is unknown. In liver of mice, the eIF2 kinase GCN2 is essential for mitigating metabolic stress caused by asparaginase. This study examined the role of GCN2 in the pancreas of mice treated with asparaginase. Eight week old wild type or GCN2 KO mice were injected once daily for 8 d with either 3 IU/g BW of saline or asparaginase. Eight hours after final injection, mice were sacrificed and pancreata were weighed and harvested. In GCN2 KO mice treated with asparaginase, pancreas weights were significantly increased (P<0.05) and the organs visibly enlarged. Histological examination revealed ductal dilatation and swollen acinar cells in GCN2 KO only. Oil red O staining and measurement of pancreas triglycerides ruled out lipid accumulation as a contributing factor. No signs of cell death by TUNEL stain were detected in the pancreas, and serum amylase activity did not differ among treatment groups. However, Pancreatitis Associated Protein (PAP) mRNA expression was elevated in livers of asparaginase-treated GCN2 KO mice only. Phosphorylation of eIF2 and pancreatic expression of asparagine synthetase were similar among treatment groups, but mTORC1 signaling was decreased to the greatest extent in the pancreata of asparaginase-treated GCN2 KO mice. Additionally, transmission electron microscopy revealed evidence of ER stress in GCN2 KO mice treated with asparaginase. These data suggest that loss of GCN2 predisposes the pancreas toward the development of asparaginase-associated pancreatitis. NIH HD070487
NoteM.S.
NoteIncludes bibliographical references
Noteby Lindsey Phillipson-Weiner
Genretheses, ETD graduate
Persistent URLhttps://doi.org/doi:10.7282/T3M90BNF
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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