Abstract
The translationally controlled tumor protein (TCTP) is upregulated in a range of cancer cell types, in part, by the activation of the mechanistic target of rapamycin (mTOR). Recently, TCTP has also been proposed to act as an indirect activator of mTOR. While it is known that mTOR plays a major role in the regulation of skeletal muscle mass, very little is known about the role and regulation of TCTP in this post-mitotic tissue. This study shows that muscle TCTP and mTOR signaling are upregulated in a range of mouse models (mdx mouse, mechanical load-induced hypertrophy, and denervation- and immobilization-induced atrophy). Furthermore, the increase in TCTP observed in the hypertrophic and atrophic conditions occurred, in part, via a rapamycin-sensitive mTOR-dependent mechanism. However, the overexpression of TCTP was not sufficient to activate mTOR signaling (or increase protein synthesis) and is thus unlikely to take part in a recently proposed positive feedback loop with mTOR. Nonetheless, TCTP overexpression was sufficient to induce muscle fiber hypertrophy. Finally, TCTP overexpression inhibited the promoter activity of the muscle-specific ubiquitin proteasome E3-ligase, MuRF1, suggesting that TCTP may play a role in inhibiting protein degradation. These findings provide novel data on the role and regulation of TCTP in skeletal muscle in vivo.
Highlights
The highly conserved translationally controlled tumor protein (TCTP; a.k.a. p21, p23, Q23, and fortilin) was initially identified as a mitogen-stimulated protein whose mRNA was found in untranslated messenger ribonucleoprotein particles [1,2,3,4,5]
TCTP was elevated at these time points in both mdx muscles compared to controls. These findings show that, similar to the hypokalemic myopathy model [38], TCTP protein is upregulated in dystrophic mdx skeletal muscle
In skeletal muscle, TCTP is not sufficient to activate mechanistic target of rapamycin (mTOR) signaling and that TCTP is unlikely to play a role as a guanine exchange factor (GEF) for the Rheb GTPase or take part in the recently proposed positive feedback loop with mTOR
Summary
The highly conserved translationally controlled tumor protein (TCTP; a.k.a. p21, p23, Q23, and fortilin) was initially identified as a mitogen-stimulated protein whose mRNA was found in untranslated messenger ribonucleoprotein particles [1,2,3,4,5]. Modelling has shown that the 5′-UTR of the TCTP mRNA contains extensive secondary structure due to a very high content (~80%) of guanine (G) and cytosine (C) nucleotides [21], a characteristic that reduces translational efficiency under www.impactjournals.com/oncotarget basal conditions, in part, by impeding ribosomal scanning and start codon recognition [22]. Combined, these data suggest that the control of TCTP protein expression is a highly regulated process that is stimulated under conditions that are associated with increased cellular growth
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