Article

S6K1- and βTRCP-Mediated Degradation of PDCD4 Promotes Protein Translation and Cell Growth

University of Virginia, Charlottesville, Virginia, United States
Science (Impact Factor: 31.48). 11/2006; 314(5798):467-71. DOI: 10.1126/science.1130276
Source: PubMed

ABSTRACT The tumor suppressor programmed cell death protein 4 (PDCD4) inhibits the translation initiation factor eIF4A, an RNA helicase
that catalyzes the unwinding of secondary structure at the 5′ untranslated region (5′UTR) of messenger RNAs (mRNAs). In response
to mitogens, PDCD4 was rapidly phosphorylated on Ser67 by the protein kinase S6K1 and subsequently degraded via the ubiquitin ligase SCFβTRCP. Expression in cultured cells of a stable PDCD4 mutant that is unable to bind βTRCP inhibited translation of an mRNA with
a structured 5′UTR, resulted in smaller cell size, and slowed down cell cycle progression. We propose that regulated degradation
of PDCD4 in response to mitogens allows efficient protein synthesis and consequently cell growth.

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    • "PDCD4 binds to the RNA helicase eIF4A and inhibits translation initiation (Suzuki et al. 2008; Loh et al. 2009). p70 S6K1 -induced phosphorylation of PDCD4 on the S67 residue has been shown to lead to the degradation of PDCD4 by the ubiquitin proteasome system, resulting in an increase in protein synthesis (Dorrello et al. 2006; Zargar et al. 2011). "
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    ABSTRACT: Skeletal muscle plays a fundamental role in mobility, disease prevention, and quality of life. Skeletal muscle mass is, in part, determined by the rates of protein synthesis, and mechanical loading is a major regulator of protein synthesis and skeletal muscle mass. The mammalian/mechanistic target of rapamycin (mTOR), found in the multi-protein complex, mTORC1, is proposed to play an essential role in the regulation of protein synthesis and skeletal muscle mass. The purpose of this review is to examine the function of mTORC1 in relation to protein synthesis and cell growth, the current evidence from rodent and human studies for the activation of mTORC1 signaling by different types of mechanical stimuli, whether mTORC1 signaling is necessary for changes in protein synthesis and skeletal muscle mass that occur in response to different types of mechanical stimuli, and the proposed molecular signaling mechanisms that may be responsible for the mechanical activation of mTORC1 signaling.
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    • "S6Ks phosphorylate components of the translational machinery and associated factors such as ribosomal protein S6, eIF4B, and PDCD4 (Banerjee et al., 1990; Dorrello et al., 2006; Kozma et al., 1990; Shahbazian et al., 2006). mTORC1 also controls energy metabolism by stimulating the activity of several transcriptional regulators such as PPARg coactivator-1a (PGC-1a), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1a (HIF-1a) (Cunningham et al., 2007; Dü vel et al., 2010; Porstmann et al., 2008). "
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    ABSTRACT: mRNA translation is thought to be the most energy-consuming process in the cell. Translation and energy metabolism are dysregulated in a variety of diseases including cancer, diabetes, and heart disease. However, the mechanisms that coordinate translation and energy metabolism in mammals remain largely unknown. The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates mRNA translation and other anabolic processes. We demonstrate that mTORC1 controls mitochondrial activity and biogenesis by selectively promoting translation of nucleus-encoded mitochondria-related mRNAs via inhibition of the eukaryotic translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs). Stimulating the translation of nucleus-encoded mitochondria-related mRNAs engenders an increase in ATP production capacity, a required energy source for translation. These findings establish a feed-forward loop that links mRNA translation to oxidative phosphorylation, thereby providing a key mechanism linking aberrant mTOR signaling to conditions of abnormal cellular energy metabolism such as neoplasia and insulin resistance.
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    • "The increased mRNA also leads to increased protein synthesis as determined by immuno-blot with antibodies directed against Drosophila Pdcd4 (Figure 2D). This is likely an underestimate of the effect since these experiments are all done under high serum and insulin conditions that should result in the rapid turnover of Pdcd4 protein (Dorrello et al., 2006). "
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    ABSTRACT: eLife digest Protein synthesis in eukaryotes occurs in two stages: transcription of DNA into messenger RNA (mRNA) in the nucleus, and then translation of that mRNA into a protein by ribosomes in the cytoplasm. These processes are regulated by a complex network of signaling pathways that enables cells to tailor protein synthesis to match current conditions. This involves regulating the expression of the genes that code for these proteins. When cells experience stressful events, such as a shortage of oxygen or nutrients, they reduce the synthesis of most proteins. This response is regulated, in part, by a signaling pathway known as the insulin and insulin-like receptor pathway. In particular, stressful events inhibit a protein complex called eIF4F, which normally initiates the translation of mRNA molecules by binding to a structure on one end of the mRNA called the 5′ cap. Despite this general inhibition, the production of certain other proteins—including the insulin receptor itself—is actually increased in response to stress. Olson et al. have carried out a series of experiments to explore how inhibition of the eIF4F protein complex influences the translation of the mRNA for the insulin receptor. The eIF4F complex is made up of three proteins, including one that binds to the 5′ cap and a helicase that unwinds the RNA. Previous work in the fruit fly Drosophila showed that translation of this mRNA can continue even if formation of the eIF4F complex is inhibited by targeting the cap binding protein. Olsen et al. now show that translation of this mRNA is also independent of the helicase. Instead, translation is maintained under these conditions because the insulin receptor mRNA contains a sequence called an internal ribosome entry site, which allows ribosomes to bind to the mRNA without the influence of the 5′ cap. Olson et al. reveal the details of this regulatory pathway in Drosophila and show that similar mechanisms are at work in mammalian cells, suggesting this pathway represents a crucial regulatory process that has been conserved during evolution. A key question for future research is whether other genes within the insulin and insulin-receptor like signaling pathway use this same trick to evade translational inhibitors. DOI: http://dx.doi.org/10.7554/eLife.00542.002
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