CPEB regulation of human cellular senescence, energy metabolism, and p53 mRNA translation

Burns, David M.; Richter, Joel D.

doi:10.1101/gad.1697808

Cited by 126 publications

(128 citation statements)

References 57 publications

(62 reference statements)

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…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. Because CPEB1 can both inhibit and activate translation, reducing the levels of CPEB1 protein would free mRNA from repression and have the same result as an increase in phosphorylation of CPEB1--namely an increase in target protein expression.…”

Section: Discussioncontrasting

confidence: 55%

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

Kochanek

Wells

2013

Molecular Cancer Research

View full text Add to dashboard Cite

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.

show abstract

Section: Discussioncontrasting

confidence: 55%

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

Kochanek

Wells

2013

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…Without negative feedback regulation of p53, the cells with severe mitochondrial dysfunction would experience bioenergetic deficits because of the repression of glycolysis by p53. The metabolic switch from OxPhos to glycolysis in the presence of reduced p53 expression supports the assumption that the p53 suppression is a viable option to meet the bioenergetic needs of cells (89). Thus, de-repression of glycolysis may be essential in mitotic cells, which may have limited OxPhos capacities (the ability to make ATP, as measured by ADP-stimulated respiration).…”

Section: Mitochondrial Dysfunction Impairs P53-mediated Cellmentioning

confidence: 63%

Mitochondrial Dysfunction Impairs Tumor Suppressor p53 Expression/Function

Compton

Kim

Griner

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Recently, mitochondria have been suggested to act in tumor suppression. However, the underlying mechanisms by which mitochondria suppress tumorigenesis are far from being clear. In this study, we have investigated the link between mitochondrial dysfunction and the tumor suppressor protein p53 using a set of respiration-deficient (Res ؊ ) mammalian cell mutants with impaired assembly of the oxidative phosphorylation machinery. Our data suggest that normal mitochondrial function is required for ␥-irradiation (␥IR)-induced cell death, which is mainly a p53-dependent process. The Res ؊ cells are protected against ␥IR-induced cell death due to impaired p53 expression/ function. We find that the loss of complex I biogenesis in the absence of the MWFE subunit reduces the steady-state level of the p53 protein, although there is no effect on the p53 protein level in the absence of the ESSS subunit that is also essential for complex I assembly. The p53 protein level was also reduced to undetectable levels in Res ؊ cells with severely impaired mitochondrial protein synthesis. This suggests that p53 protein expression is differentially regulated depending upon the type of electron transport chain/respiratory chain deficiency. Moreover, irrespective of the differences in the p53 protein expression profile, ␥IR-induced p53 activity is compromised in all Res ؊ cells. Using two different conditional systems for complex I assembly, we also show that the effect of mitochondrial dysfunction on p53 expression/function is a reversible phenomenon. We believe that these findings will have major implications in the understanding of cancer development and therapy.Mitochondrial dysfunction is associated with aging, degenerative diseases, and cancer (1-3). One of the key functions of mitochondria is to make ATP by the process of oxidative phosphorylation (OxPhos), 2 which is carried out by four electron transport chain (ETC)/respiratory chain (RC) complexes (I-IV) and the ATP synthase (complex V). The OxPhos machinery consists of over 100 nuclear and mitochondrial DNA-encoded proteins (4). Thirteen proteins encoded by mitochondrial (mt) DNA are core proteins of complexes I and III-V that are synthesized inside mitochondria. Complex II is an exception as all of its subunits are encoded by nuclear genes. Mutations in both mtDNA and nuclear genes encoding OxPhos complexes are associated with almost all types of cancers (1, 3). Somatic mutations in complex I subunit-encoding genes are frequently associated with oncocytomas (5, 6). A recent study with head and neck cancers suggests that there are no mutational hot spots in the mtDNA (7). However, other studies suggest that mtDNA polymorphisms may predispose certain populations to cancer (8 -12). The association of germ line mutations in complex II subunits with hereditary paragangliomas and pheochromocytomas constitute the strongest evidence for implicating mitochondrial metabolism in tumorigenesis (13,14). Furthermore, the association of reduced expression of several subunits of OxPhos comple...

show abstract

“…Thus, the translational repression of myc by CPEB1 is a key event in promoting senescence in MEFs (2). Similarly, in human lung and skin fibroblast primary culture, absence of CPEB1 causes a bypass of senescence accompanied by extended cellular life span, which indicates CPEB1 is required to stimulate senescence (2,28,29).…”

Section: Cpeb1mentioning

confidence: 99%

“…CPEB1 requires p53, p19 ARF and p16 ARF to induce senescence, since exogenous CPEB1 could not induce senescence in p53, p19 ARF or p16 ARF /p19 ARF double knockout MEFs (2). Reduced p53 mRNA polyadenylation and translation cause senescence bypass in CPEB1-depleted cells (28). Furthermore, CPEB1 also controls the cytoplasmic polyadenylation of human P53 mRNA by elongation of its poly(A) tail, while CPEB1 knockdown results in deficient polyadenylation of p53 mRNA and about 50% reduction of p53 protein levels (1,28).…”

Section: Cpeb1mentioning

confidence: 99%

“…Reduced p53 mRNA polyadenylation and translation cause senescence bypass in CPEB1-depleted cells (28). Furthermore, CPEB1 also controls the cytoplasmic polyadenylation of human P53 mRNA by elongation of its poly(A) tail, while CPEB1 knockdown results in deficient polyadenylation of p53 mRNA and about 50% reduction of p53 protein levels (1,28). These results suggest CPEB1 plays a significant role for inducing cellular senescence and its functions are closely related to the functions of p53, p19 ARF or p16 ARF /p19 ARF .…”

Section: Cpeb1mentioning

confidence: 99%

See 1 more Smart Citation

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

Chen

Tsai

Tseng

2016

View full text Add to dashboard Cite

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

show abstract

CPEB regulation of human cellular senescence, energy metabolism, and p53 mRNA translation

Abstract: [Keywords: CPEB; senescence; polyadenylation; translation; bioenergetics; p53] Supplemental material is available at http://www.genesdev.org.

Cited by 126 publications

References 57 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

Mitochondrial Dysfunction Impairs Tumor Suppressor p53 Expression/Function

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

Contact Info

Product

Resources

About