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Kim, Dong Eun (2011) THE ROLE OF THE N-END RULE PATHWAY IN CARDIOVASCULAR DEVELOPMENT, SIGNALING, AND HOMEOSTASIS. Master's Thesis, University of Pittsburgh. (Unpublished)

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The N-end rule pathway relates the in vivo half-life of a protein to the identity of its N-terminal residue. The conjugation of arginine (Arg) from Arg-tRNAArg to N-terminal Asp, Glu, or Cys is a universal eukaryotic protein modification that can lead to ubiquitylation and proteasomal degradation of the resulting Arg-conjugated proteins through the N-end rule pathway. The mammalian ATE1 gene encodes Arg-transferase that mediates all known N-terminal arginylation reactions. ATE1-/- embryos die owing to various cardiovascular defects including ventricular hypoplasia, ventricular septal defect, and late angiogenesis. The genomewide functional proteomics previously identified a set of RGS proteins (RGS4, RGS5, and RGS16) as in vivo substrates of ATE1. These RGS proteins are important negative regulators of Gáq-activated signaling for myocardial growth and vascular maturation/integrity. In my first project, I attempted to determine the role of ATE1-dependent posttranslational arginylation in Gáq-dependent cardiac signaling. I constructed and characterized ATE1-/-GáqTg compound mutant mice, where Gáq is exclusively overexpressed in the heart from áMHC promoter. I found that while Gáq overexpression in the heart rescues significantly cardiac defects in ATE1-/- embryonic hearts, it does not cause a noticeable change in vascular defects. These results together suggest that ATE1 controls cardiac development and signaling in part through Gq-activated signaling pathways. In the second project, I generated RGS5 transgenic mouse (TG) strains overexpressing either MC-RGS5 (wild-type, short-lived) or MV-RGS5 (mutant, long-lived) from vascular smooth muscle-specific SM22á promoter to determine the physiological importance of RGS5 proteolysis in Gq signaling of VSMC. Both MC-RGS5 and MV-RGS5 mice were viable and fertile without any visible defects. However, MC-RGS5 femalevmice demonstrated impaired delivery in that newborn pups were often found dead associated with an absence of milk in their stomachs. In contrast, MV-RGS5 mice did not show this phenotype. The mis-regulated RGS5 proteolysis in MC-RGS5 mice may result in the failure in oxytocin-induced uterine and mammary gland smooth muscle contraction. In summary, my research provides an insight into the role of N-end rule pathway in cardiovascular Gq signaling.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Kim, Dong Eundek30@pitt.eduDEK30
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVollmer, Regis Rvollm@pitt.eduVOLLM
Committee MemberIsenberg, Jeffreyjsi5@pitt.eduJSI5
Committee MemberLi, Songsol4@pitt.eduSOL4
Committee MemberLee, Yong Jleeyj@pitt.eduLEEYJ
Committee MemberKwon, Yong Taeyok5@pitt.eduYOK5
Date: 10 January 2011
Date Type: Completion
Defense Date: 6 October 2010
Approval Date: 10 January 2011
Submission Date: 6 October 2010
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: ATE1; cardiovascular system; GPCR; N-end rule pathway; RGS5; transgenic mice; ubiquitin system
Other ID:, etd-10062010-201104
Date Deposited: 10 Nov 2011 20:02
Last Modified: 15 Nov 2016 13:50


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