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Signaling Pathways that Regulate Autophagic Muscle Protein Degradation in C. elegans

Bialas, Chris (2010) Signaling Pathways that Regulate Autophagic Muscle Protein Degradation in C. elegans. Undergraduate Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Protein degradation in C. elegans muscle cells is very tightly controlled by opposing signaling cascades. Excessive FGFR, low IGFR or TGF-B signaling, starvation or denervation all lead to muscle protein breakdown. Here we show that under conditions of activated FGFR, low IGFR or low TGF-B activity or mutationally hyperactived MAP kinase, soluble protein in muscle cytosol is degraded through autophagy. Degradation under these conditions is prevented by a reduction of function mutation in unc-51 (encodes Atg1 homologue), by RNAi knockdown of BEC-1 (beclin), or ATG-7 (Atg7 homologue) or by treatment with N6,N6-dimethyladenosine, a presumed inhibitor of type III PtdIns-3-kinase. We infer that the MAP kinase cascade positively regulates autophagy when the FGFR signal is too high or the IGFR signal too low . However, we have yet to identify how a MAPK signal plays into TGF-B regulation of autophagy. Protein degradation following starvation or disruption of cholinergic signaling (ACh-deficient cha-1 mutant) is not prevented by interference with autophagy, consistent with the known sensitivity to proteasome inhibitors. We have also implicated the signaling protein RSK as necessary for autophagic signaling either in parallel with or downstream of MAPK The metabolic reserve of protein in muscle can be mobilized by catabolism in response to failure of any one of a variety of signals of 'healthy' conditions. To achieve versatility and flexibility of response, muscle cells evidently use multiple proteolytic systems and regulate them independently by integrating more than one regulatory input to each degradation system.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Bialas, Chriscpb10@pitt.eduCPB10
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairJacobson, Lewljac@pitt.eduLJAC
Committee MemberLink, Chris
Committee MemberBoyle, Johnboylej@pitt.eduBOYLEJ
Committee MemberKiselyov, Kirillkiselyov@pitt.eduKISELYOV
Date: 13 May 2010
Date Type: Completion
Defense Date: 10 April 2010
Approval Date: 13 May 2010
Submission Date: 29 April 2010
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
University Honors College
Degree: BPhil - Bachelor of Philosophy
Thesis Type: Undergraduate Thesis
Refereed: Yes
Uncontrolled Keywords: atrophy; FGF; FGFR; IGF; IGFR; LacZ; MAPK; proteolysis; RNAi; TGF-B; worms
Other ID: http://etd.library.pitt.edu/ETD/available/etd-04292010-130408/, etd-04292010-130408
Date Deposited: 10 Nov 2011 19:43
Last Modified: 15 Nov 2016 13:42
URI: http://d-scholarship.pitt.edu/id/eprint/7730

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