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A role for the mRNA-stabilizing protein HuR in protection from cellular ATP depletion

Jeyaraj, Selvi Chrysolyte
http://rave.ohiolink.edu/etdc/view?acc_num=osu1186773861

Abstract Details

2007, Doctor of Philosophy, Ohio State University, Molecular, Cellular, and Developmental Biology.
The regulation of gene expression is a multi level process that is essential to cellular processes. V-ATPases are multisubunit membrane proteins that use ATP binding and hydrolysis to transport protons across membranes against a concentration gradient. It has been previously shown that mRNA stability appears to play a major role in regulating overall abundance of V-ATPases. Human antigen R (HuR) is a nucleocytoplasmic shuttling protein that binds to and stabilizes mRNAs containing adenine- and uridine-rich elements. HuR shows increased binding to some V-ATPase mRNAs during ATP depletion. The behavior of HuR in LLC-PK1 proximal tubule cells was studied when subjected to ATP depletion and recovery. ATP depletion resulted in detectable net movement of HuR out of the nucleus, followed by net movement of HuR back into the nucleus on reversion to normal growth medium. In addition, HuR protein levels increased during energy depletion. In contrast, recovery in normal growth medium resulted in increased HuR mRNA, while protein levels decreased to baseline. This suggested a mechanism by which previously injured cells maintained normal levels of HuR but were primed to rapidly translate increased amounts of protein on subsequent insults. Indeed, a second round of ATP depletion resulted in heightened HuR protein translation at a rate more rapid than during the first insult. During normal, ATP depletion, and recovery conditions, there are three forms of HuR 5’-untranslated regions expressed. Promoter analysis of HuR upstream regions revealed two regions necessary for the upregulation of mRNA during recovery. Analysis of the porcine and murine 5’-UTR reveals the existence of the Smad 1/5/8 binding motif GCCGnCGC, respectively. During 4 hours of recovery there is a marked increase in Smad phosphorylation accompanied by relocalization of Smads to the nucleus where they act as transcriptional activators. Indeed, activation of Smads with BMP-7, a member of the TGF-β superfamily of signaling molecules, caused an increase in HuR mRNA levels. These data suggest that the preconditioning response of HuR mRNA may be driven by a mechanism known to protect the kidney from injury and provides a novel pathway through which administration BMP-7 may attenuate renal damage.
Beth Lee (Advisor)

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Citations

  • Jeyaraj, S. C. (2007). A role for the mRNA-stabilizing protein HuR in protection from cellular ATP depletion [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1186773861

    APA Style (7th edition)

  • Jeyaraj, Selvi. A role for the mRNA-stabilizing protein HuR in protection from cellular ATP depletion. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1186773861.

    MLA Style (8th edition)

  • Jeyaraj, Selvi. "A role for the mRNA-stabilizing protein HuR in protection from cellular ATP depletion." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1186773861

    Chicago Manual of Style (17th edition)

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© 2007, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.