Key contribution of CPEB4-mediated translational control to cancer progression

Ortiz-Zapater, Elena; Pineda, David; Martínez-Bosch, Neus; Fernández-Miranda, Gonzalo; Iglesias, Mar; Alameda, Francesc; Moreno, Mireia; Eliscovich, Carolina; Eyras, Eduardo; Real, Francisco X.; Méndez, Raúl; Navarro, Pilar

doi:10.1038/nm.2540

Cited by 136 publications

(190 citation statements)

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“…In agreement with a role for CPEB in tumor growth, the CPEB1 paralog CPEB4 regulates the translation of a group of proteins necessary for pancreatic ductal adenocarcinoma growth, invasion, and vascularization (28). Originally thought to differ in their mRNA targets (29), recent studies have shown that CPEB4 does recognize and bind to some of the same CPE targets as CPEB1, though with a lower affinity (30,31).…”

Section: Discussionmentioning

confidence: 88%

“…Originally thought to differ in their mRNA targets (29), recent studies have shown that CPEB4 does recognize and bind to some of the same CPE targets as CPEB1, though with a lower affinity (30,31). For example, like CPEB1 in hippocampal neurons, CPEB4 has been shown to bind and regulate tPA in both normal and cancerous pancreatic tissue (28). Interestingly, several reports implicate a downregulation of CPEB1 in cancer (32)(33)(34), whereas the results presented here suggest that an increase in CPEB1-mediated translation may support the progression of cancer.…”

Section: Discussionmentioning

confidence: 99%

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CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

Kochanek

Wells

2013

Molecular Cancer Research

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Cytoplasmic polyadenylation element-binding protein 1 (CPEB1) is an mRNA-binding protein present in both neurons and glia. CPEB1 is capable of both repressing mRNA translation and activating it depending upon its phosphorylation state. CPEB1-bound mRNAs are held in translational dormancy until CPEB1 is phosphorylated, leading to the cytoplasmic polyadenylation of the bound mRNA that triggers translation. Here, we show that CPEB1 can bind to and regulate translation of the mRNA-encoding metadherin (MTDH, also known as AEG-1 and Lyric) in the rat glioblastoma cell line CNS1. MTDH/AEG-1 is being revealed as a critical signaling molecule in tumor progression, playing roles in invasion, metastasis, and chemoresistance. By using a mutant of CPEB1 that cannot be phosphorylated (thereby holding target mRNAs in translational arrest), we show that inhibiting CPEB1-mediated translation blocks MTDH/AEG-1 expression in vitro and inhibits glioblastomas tumor growth in vivo. CPEB1-mediated translation is likely to impact several signaling pathways that may promote tumor progression, but we present evidence suggesting a role in directed cell migration in glioblastoma cells. In addition, reporter mRNA containing CPEB1-binding sites is transported to the leading edge of migrating cells and translated, whereas the same mRNA with point mutations in the binding sites is synthesized perinuclearly. Our findings show that CPEB1 is hyperactive in rat glioblastoma cells and is regulating an important cohort of mRNAs whose increased translation is fueling the progression of tumor proliferation and dispersal in the brain. Thus, targeting CPEB1-mediated mRNA translation might be a sound therapeutic approach. Mol Cancer Res; 11(2); 149-60. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

Kochanek

Wells

2013

Molecular Cancer Research

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“…This variant is located approximately 400 kb from HMGCR3, involved in lipid metabolism and shown to be associated with total cholesterol [32]. The biological mechanisms by which the remaining obesity-susceptibility loci might affect glucose (RBJ, CPEB4) and lipid metabolism (MTCH2) are less well understood [40][41][42] and require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Pleiotropic effects of obesity-susceptibility loci on metabolic traits: a meta-analysis of up to 37,874 individuals

et al. 2013

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Aims/hypothesis Genetic pleiotropy may contribute to the clustering of obesity and metabolic conditions. We assessed whether genetic variants that are robustly associated with BMI and waist-to-hip ratio (WHR) also influence metabolic and cardiovascular traits, independently of obesity-related traits, in meta-analyses of up to 37,874 individuals from six European population-based studies. Methods We examined associations of 32 BMI and 14 WHR loci, individually and combined in two genetic predisposition scores (GPSs), with glycaemic traits, blood lipids and BP, with and without adjusting for BMI and/or WHR. Results We observed significant associations of BMIincreasing alleles at five BMI loci with lower levels of 2 h glucose (RBJ [also known as DNAJC27], QPTCL: effect sizes −0.068 and −0.107 SD, respectively), HDL-cholesterol (SLC39A8: −0.065 SD, MTCH2: −0.039 SD), and diastolic BP (SLC39A8: −0.069 SD), and higher and lower levels of LDL-and total cholesterol (QPTCL: 0.041 and 0.042 SDs, respectively, FLJ35779 [also known as POC5]: −0.042 and −0.041 SDs, respectively) (all p<2.4×10 −4 ), independent of BMI. The WHR-increasing alleles at two WHR loci were significantly associated with higher proinsulin (GRB14: 0.069 SD) and lower fasting glucose levels (CPEB4: −0.049 SD), independent of BMI and WHR. A higher GPS-BMI was associated with lower systolic BP (−0.005 SD), diastolic BP (−0.006 SD) and 2 h glucose (−0.013 SD), while a higher GPS-WHR was associated with lower HDL-cholesterol Electronic supplementary material The online version of this article (doi:10.1007/s00125-013-2985-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users. J. V. van Vliet-Ostaptchouk : M. M. van der Klauw :

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“…Cancer development is closely related to the reprogramming of gene expression and genetic derangement contributes to cell proliferation, apoptosis, metabolism, invasion and malignant transformation (18,19). CPEBs control cellular proliferation, chromosome segregation and cell differentiation; aberrant expression of CPEBs correlates with certain types of cancer, indicating that cytoplasmic RNA 3' end processing is important in the control of tumor cell growth (1,19,20).…”

Section: Cpebs and Cancermentioning

confidence: 99%

“…CPEBs control cellular proliferation, chromosome segregation and cell differentiation; aberrant expression of CPEBs correlates with certain types of cancer, indicating that cytoplasmic RNA 3' end processing is important in the control of tumor cell growth (1,19,20). Several CPEBregulated mRNAs regulate cell-cycle progression, senescence and cell polarity (20).…”

Section: Cpebs and Cancermentioning

confidence: 99%

Regulation of the Expression of Cytoplasmic Polyadenylation Element Binding Proteins for the Treatment of Cancer

Chen

Tsai

Tseng

2016

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Abstract. Regulated mRNA translation plays an important role in normal cellular functions and cytoplasmic polyadenylation element binding proteins (CPEBs) are the key factors that control the elongation of poly(A) tail during translation. The expression of various Translation and Cytoplasmic Polyadenylation Element Binding Proteins (CPEBs)Regulated mRNA translation plays an important role in normal cellular functions (1, 2). The translation of an mRNA is divided into three steps: initiation, elongation and termination (1). Among them, translation initiation is the rate-limiting, the most complex and the main target for translational control mechanisms (3). The 5'end of all transcribed mRNAs contains a 5'cap and the other end is blocked by a long stretch, usually in the order of 200-500 nucleotides of adenine residues (poly(A) tail) (1). Both the cap and the poly(A) tail of mRNAs act synergistically to facilitate translation (1). The translation is affected by a number of factors that stimulate or inhibit the translation of specific mRNAs (1, 2). Among these factors, RNAbinding proteins that recognize specific motifs in the 3' untranslated region (3'UTR) of their targets, are important (1, 2, 4). Of these RNA-binding proteins, cytoplasmic polyadenylation element binding protein (CPEB) family are sequence-specific RNA-binding proteins and the key factors controling the elongation of the poly(A) tail and polyadenylation-induced translation (2,5,6). CPEB binds the cytoplasmic polyadenylation element (CPE) in the 3' untranslated regions of responding mRNAs (2, 7-9). CPEB-mediated effects on translation require at least two CPEs separated by less than 50 nucleotides in the target mRNA, which indicates the formation of CPEB-dimer (10). CPEBs can recruit the translational repression or cytoplasmic polyadenylation machineries to their target mRNAs and nucleate a complex of factors that regulates poly(A) elongation through a deadenylating enzyme (1,4,7,(11)(12)(13). 5673

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Key contribution of CPEB4-mediated translational control to cancer progression

Cited by 136 publications

References 56 publications

CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

Pleiotropic effects of obesity-susceptibility loci on metabolic traits: a meta-analysis of up to 37,874 individuals

Regulation of the Expression of Cytoplasmic Polyadenylation Element Binding Proteins for the Treatment of Cancer

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