The role of protein synthesis in cell cycling and cancer

White‐Gilbertson, Shai; Kurtz, David T.; Voelkel‐Johnson, Christina

doi:10.1016/j.molonc.2009.05.003

Cited by 74 publications

(66 citation statements)

References 40 publications

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“…Protein translation is concertedly ruled, and deregulation at any step of translational control might predispose cells to transformation or deteriorate tumor progression (20,42). The oncogene c-Myc enhances protein translation through transactivating diverse targets, such as initiation factors, ribosomal proteins, and rRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…Increased ribosome production coupled to elevated protein translation facilitates cell growth and proliferation, and crucially contributes to tumor progression (19,42). Studies have demonstrated that elevated rRNA synthesis is closely associated with cell transformation and cell proliferation, and a few rRNAs are overexpressed in cancers, such as prostate cancer, gastric cancer, and breast cancer (22,37).…”

Section: Discussionmentioning

confidence: 99%

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HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

Zhang

Yin

Wang

et al. 2014

Molecular Cancer Research

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Activation of c-Myc plays a decisive role in the development of many human cancers. As a transcription factor, cMyc facilitates cell growth and proliferation by directly transcribing a multitude of targets, including rRNAs and ribosome proteins. However, how to elucidate the deregulation of rRNAs and ribosome proteins driven by c-Myc in cancer remains a significant challenge and thus warrants close investigation. In this report, a crucial role for the HSPC111 (NOP16) multiprotein complex in governing ribosomal biogenesis and tumor growth was determined. It was discovered that enhanced HSPC111 expression paralleled the upregulation of c-Myc and was directly regulated by c-Myc in breast cancer cells. Knockdown of HSPC111 dramatically reduced the occurrence of tumorigenesis in vivo, and largely restrained tumor cell growth in vitro and in vivo. In stark contrast, HSPC111 overexpression significantly promoted tumor cell growth. Biochemically, it was demonstrated that RNA 3 0 -phosphate cyclase (RTCD1/RTCA) interacted with HSPC111, and RTCD1 was involved in the HSPC111 multiprotein complex in regulating rRNA production and ribosomal biogenesis. Moreover, HSPC111 and RTCD1 synergistically modulated cell growth and cellular size through commanding rRNA synthesis and ribosome assembly coupled to protein production. Finally, overall survival analysis revealed that concomitant upregulation of HSPC111 and RTCD1 correlated with the worst prognosis in a breast cancer cohort.Implications: Inhibition of HSPC111-dependent ribosomal biosynthesis and protein synthesis is a promising therapeutic strategy to diminish breast cancer tumor progression. Mol Cancer Res; 12(4); 583-94. Ó2014 AACR. IntroductionBreast cancer is by far the most common cancer among women and the leading cause of cancer-related deaths worldwide. The primary tumor and metastases to distant organs often cause significant morbidity and mortality. Numerous studies suggest that the oncogene c-Myc plays a crucial role in the development and progression of breast cancer. Along with its partner protein Max, c-Myc regulates an estimated 10% to 15% of genes in the human genome, and globally reprograms cells and drives proliferation (1-3). Aberrant regulation and overexpression of c-Myc are observed in most tumor types,

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

Zhang

Yin

Wang

et al. 2014

Molecular Cancer Research

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“…Moreover, ONTAK and its predecessor, DAB486IL-2 (Le Maistre et al, 1992) have demonstrated activity in a variety of diseases, including cutaneous T cell lymphoma (CTCL), psoriasis, rheumatoid arthritis and HIV infection. Hence, DT-based fusion toxins are important biological agents for the treatment of certain tumours or disorders in which specific cell surface receptors can be selectively targeted (Hesketh et al, 1993;Van der Spek et al, 1994;Foss, 2001;Kreitman, 2006Kreitman, , 2009 and it is likely that such DT chimera will be providing further and important new biological tools for selected cell targeting and DT-dependent inactivation of protein biosynthesis, a fundamental biological process with key roles for cell cycling and cancer formation (White-Gilbertson et al, 2009). …”

Section: Engineering Dt Chimera For Use In Cell-specific Proliferatiomentioning

confidence: 99%

“…Here, we review recent advances in the molecular biology of DT and present new insights into DT mode of action and DT response pathway components. An attractive idea emerging from research into DT mode of action is to take its basic molecular biology and apply it to biomedical intervention schemes against tumour cells, microbial pathogens or other biomedically and biotechnically relevant cell systems whose proliferation heavily relies on mRNA translation and protein biosynthesis (White-Gilbertson et al, 2009;Uthman et al, 2011). Such strategies are particularly informed by the use of chimeric DT fusion proteins that combine the lethal ADP-ribosylation activity of DT with a specific cell surface receptor domain for target cell or tissue specificity (Kreitman, 2006(Kreitman, , 2009.…”

Section: Introductionmentioning

confidence: 99%

Diphtheria Disease and Genes Involved in Formation of Diphthamide, Key Effector of the Diphtheria Toxin

Uthman¹,

Liu²,

Giorgini³

et al. 2012

Insight and Control of Infectious Disease in Global Scenario

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“…A single, atypical calmodulin-dependent kinase, termed eEF2 kinase (eEF2K), phosphorylates eEF2 on T56 (10)(11)(12). Many signals cause eEF2K to become phosphorylated on residues that inhibit or augment its activity (5,13,14). For example, the mitogen-activated protein kinase (MAPK) and mTOR pathways inhibit eEF2K in response to mitogen and nutrient signals (15)(16)(17).…”

mentioning

confidence: 99%

Phosphorylation of Eukaryotic Elongation Factor 2 (eEF2) by Cyclin A–Cyclin-Dependent Kinase 2 Regulates Its Inhibition by eEF2 Kinase

Hizli

Chi

Swanger

et al. 2013

Molecular and Cellular Biology

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Protein synthesis is highly regulated via both initiation and elongation. One mechanism that inhibits elongation is phosphorylation of eukaryotic elongation factor 2 (eEF2) on threonine 56 (T56) by eEF2 kinase (eEF2K). T56 phosphorylation inactivates eEF2 and is the only known normal eEF2 functional modification. In contrast, eEF2K undergoes extensive regulatory phosphorylations that allow diverse pathways to impact elongation. We describe a new mode of eEF2 regulation and show that its phosphorylation by cyclin A-cyclin-dependent kinase 2 (CDK2) on a novel site, serine 595 (S595), directly regulates T56 phosphorylation by eEF2K. S595 phosphorylation varies during the cell cycle and is required for efficient T56 phosphorylation in vivo. Importantly, S595 phosphorylation by cyclin A-CDK2 directly stimulates eEF2 T56 phosphorylation by eEF2K in vitro, and we suggest that S595 phosphorylation facilitates T56 phosphorylation by recruiting eEF2K to eEF2. S595 phosphorylation is thus the first known eEF2 modification that regulates its inhibition by eEF2K and provides a novel mechanism linking the cell cycle machinery to translational control. Because all known eEF2 regulation is exerted via eEF2K, S595 phosphorylation may globally couple the cell cycle machinery to regulatory pathways that impact eEF2K activity. G lobal protein synthesis is subject to complex regulation that allows cells to control this energy-intensive process in response to diverse physiologic cues. Translation is regulated at the initiation and elongation levels. For example, translation is repressed in the G 2 /M phase of the cell cycle (1, 2), in which inhibition of eukaryotic initiation factors represses mitotic translation (2-4). Translational control is also exerted at the level of elongation, and this often involves inhibition of eukaryotic elongation factor 2 (eEF2) (5-7).eEF2 is a GTP-dependent translocase that is responsible for the movement of nascent peptidyl-tRNAs from the A-site to the P-site of the ribosome. The only known normal mechanism that regulates eEF2 is an inhibitory phosphorylation at threonine 56 (T56), which falls within the eEF2 GTP-binding domain and prevents eEF2 from binding to the ribosome (8, 9). A single, atypical calmodulin-dependent kinase, termed eEF2 kinase (eEF2K), phosphorylates eEF2 on T56 (10-12). Many signals cause eEF2K to become phosphorylated on residues that inhibit or augment its activity (5,13,14). For example, the mitogen-activated protein kinase (MAPK) and mTOR pathways inhibit eEF2K in response to mitogen and nutrient signals (15-17). In contrast, AMP kinase-and protein kinase A/Ca 2ϩ -dependent signaling activates eEF2K in response to starvation, hypoxia, and oxidative stress (18-21). Thus, while many signaling pathways control eEF2 activity, this regulation is exerted exclusively via modification of eEF2K rather than eEF2. T56 phosphorylation is thus the only known eEF2 functional modification, other than its inhibition by ADP ribosylation catalyzed by bacterial toxins (6).Cyclin-dependent kinas...

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The role of protein synthesis in cell cycling and cancer

Cited by 74 publications

References 40 publications

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

Diphtheria Disease and Genes Involved in Formation of Diphthamide, Key Effector of the Diphtheria Toxin

Phosphorylation of Eukaryotic Elongation Factor 2 (eEF2) by Cyclin A–Cyclin-Dependent Kinase 2 Regulates Its Inhibition by eEF2 Kinase

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