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Isoform-specific SCF(Fbw7) ubiquitination mediates differential regulation of PGC-1?.


ABSTRACT: The E3 ubiquitin ligase and tumor suppressor SCF(Fbw7) exists as three isoforms that govern the degradation of a host of critical cell regulators, including c-Myc, cyclin E, and PGC-1?. Peroxisome proliferator activated receptor-gamma coactivator 1? (PGC-1?) is a transcriptional coactivator with broad effects on cellular energy metabolism. Cellular PGC-1? levels are tightly controlled in a dynamic state by the balance of synthesis and rapid degradation via the ubiquitin-proteasome system. Isoform-specific functions of SCF(Fbw7) are yet to be determined. Here, we show that the E3 ubiquitin ligase, SCF(Fbw7), regulates cellular PGC-1? levels via two independent, isoform-specific, mechanisms. The cytoplasmic isoform (SCF(Fbw7?)) reduces cellular PGC-1? levels via accelerated ubiquitin-proteasome degradation. In contrast, the nuclear isoform (SCF(Fbw7?)) increases cellular PGC-1? levels and protein stability via inhibition of ubiquitin-proteasomal degradation. When nuclear Fbw7? proteins are redirected to the cytoplasm, cellular PGC-1? protein levels are reduced through accelerated ubiquitin-proteasomal degradation. We find that SCF(Fbw7?) catalyzes high molecular weight PGC-1?-ubiquitin conjugation, whereas SCF(Fbw7?) produces low molecular weight PGC-1?-ubiquitin conjugates that are not effective degradation signals. Thus, selective ubiquitination by specific Fbw7 isoforms represents a novel mechanism that tightly regulates cellular PGC-1? levels. Fbw7 isoforms mediate degradation of a host of regulatory proteins. The E3 ubiquitin ligase, Fbw7, mediates PGC-1? levels via selective isoform-specific ubiquitination. Fbw7? reduces cellular PGC-1? via ubiquitin-mediated degradation, whereas Fbw7? increases cellular PGC-1? via ubiquitin-mediated stabilization.

SUBMITTER: Trausch-Azar JS 

PROVIDER: S-EPMC4596538 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Isoform-specific SCF(Fbw7) ubiquitination mediates differential regulation of PGC-1α.

Trausch-Azar Julie S JS   Abed Mona M   Orian Amir A   Schwartz Alan L AL  

Journal of cellular physiology 20150401 4


The E3 ubiquitin ligase and tumor suppressor SCF(Fbw7) exists as three isoforms that govern the degradation of a host of critical cell regulators, including c-Myc, cyclin E, and PGC-1α. Peroxisome proliferator activated receptor-gamma coactivator 1α (PGC-1α) is a transcriptional coactivator with broad effects on cellular energy metabolism. Cellular PGC-1α levels are tightly controlled in a dynamic state by the balance of synthesis and rapid degradation via the ubiquitin-proteasome system. Isofor  ...[more]

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