CPEB Degradation during Xenopus Oocyte Maturation Requires a PEST Domain and the 26S Proteasome

Reverte, Carlos G.; Ahearn, Michael D.; Hake, Laura E.

doi:10.1006/dbio.2001.0153

Cited by 84 publications

(70 citation statements)

References 57 publications

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“…Another interesting feature of the SIRT1 protein is the presence of the PEST sequence at residues 525-550 and 667-697. The PEST sequence acts as a signal peptide for protein degradation, and this cleavage is possibly mediated via the proteasome or calpain (56,57). The presence of two PEST regions in SIRT1 is correlated with rapid degradation of the protein by 26 S proteasome protease.…”

Section: Discussionmentioning

confidence: 99%

Ionizing Radiation Induces Cellular Senescence of Articular Chondrocytes via Negative Regulation of SIRT1 by p38 Kinase

Hong

Lee

Kim

et al. 2010

Journal of Biological Chemistry

147

123

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Radiotherapy is increasingly used in the treatment of joint diseases, but limited information is available on the effects of radiation on cartilage. Here, we characterize the molecular mechanisms leading to cellular senescence in irradiated primary cultured articular chondrocytes. Ionizing radiation (IR) causes activation of ERK, in turn generating intracellular reactive oxygen species (ROS) with induction of senescence-associated ␤-galactosidase (SA-␤-gal) activity. ROS activate p38 kinase, which further promotes ROS generation, forming a positive feedback loop to sustain ROS-p38 kinase signaling. The ROS inhibitors, nordihydroguaiaretic acid and GSH, suppress phosphorylation of p38 and cell numbers positive for SA-␤-gal following irradiation. Moreover, inhibition of the ERK and p38 kinase pathways leads to blockage of IR-induced SA-␤-gal activity via reduction of ROS generation. Although JNK is activated by ROS, this pathway is not associated with cellular senescence of chondrocytes. Interestingly, IR triggers down-regulation of SIRT1 protein expression but not the transcript level, indicative of post-transcriptional cleavage of the protein. SIRT1 degradation is markedly blocked by SB203589 or MG132 after IR treatment, suggesting that cleavage occurs as a result of binding with p38 kinase, followed by processing via the 26 S proteasomal degradation pathway. Overexpression or activation of SIRT1 significantly reduces the IR-induced senescence phenotype, whereas inhibition of SIRT1 activity induces senescence. Based on these findings, we propose that IR induces cellular senescence of articular chondrocytes by negative post-translational regulation of SIRT1 via ROS-dependent p38 kinase activation.

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Section: Discussionmentioning

confidence: 99%

Ionizing Radiation Induces Cellular Senescence of Articular Chondrocytes via Negative Regulation of SIRT1 by p38 Kinase

Hong

Lee

Kim

et al. 2010

Journal of Biological Chemistry

147

123

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“…Because the molecular structure of CPEB has been thoroughly examined (26,27), further structure/ function analysis with previously characterized deletion mutants of CPEB allowed us to identify which CPEB functions are most critical for different aspects of neuronal development and circuit function. Using time-lapse imaging, we found that expressing delCPEB, which interferes with CPEB's activity-dependent mRNA polyadenylation but leaves dendritic mRNA transport intact, impairs dendritic-arbor development and the integration of neurons into the visual circuit.…”

Section: Discussionmentioning

confidence: 99%

“…The second deletion mutant (delCPEB; ⌬124-258) lacks the phosphorylation site targeted by aurora kinase and ␣CaMKII. Because it is not activated by phosphorylation (26,27), delCPEB can stably bind and transport mRNA (28) but interferes with the activity-dependent polyadenylation and translation initiation of CPEB mRNA targets. We verified in the retinotectal system that expression of delCPEB interferes with CPEB-dependent protein synthesis in a blind study that compared tissue plasminogen activator (tPA) immunofluorescence in tectal cells expressing del-CPEB, CPEB1, or YFP alone with untransfected neighboring neurons (Fig.…”

mentioning

confidence: 99%

The RNA binding protein CPEB regulates dendrite morphogenesis and neuronal circuit assembly in vivo

Bestman

Cline

2008

Proc. Natl. Acad. Sci. U.S.A.

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Visual system development requires experience-dependent mechanisms that regulate neuronal structure and function, including dendritic arbor growth, synapse formation, and stabilization. Although RNA binding proteins have been shown to affect some forms of synaptic plasticity in adult animals, their role in the development of neuronal structure and functional circuitry is not clear. Using two-photon time-lapse in vivo imaging and electrophysiology combined with morpholino-mediated knockdown and expression of functional deletion mutants, we demonstrate that the mRNA binding protein, cytoplasmic polyadenylation element binding protein1 (CPEB1), affects experience-dependent neuronal development and circuit formation in the visual system of Xenopus laevis. These data indicate that sensory experience controls circuit development by regulating translational activity of mRNAs.circuit integration ͉ experience-dependent plasticity ͉ in vivo imaging ͉ visual system ͉ whole-cell recording D uring CNS development, neuronal structure, synaptic connections, and circuit functions change in response to sensory input. Although the regulation of mRNA translation and new protein synthesis have been implicated in some forms of neuronal plasticity in adult animals (1, 2), their role in experience-dependent sensory system plasticity has not been addressed (3). In the brain, the translation of many mRNAs is regulated by their association with ribonucleoprotein (RNP) granules, which are composed of core RNA binding proteins, translational machinery, and mRNAs (4). RNA binding proteins package specific mRNAs within RNP granules, regulate their transport into dendrites, and in principle, could temporally and spatially govern their translation in response to synaptic activity (4). Because of these features, mRNA binding proteins are in a unique position to control developmental events through the coordinated translation of a functionally related cohort of mRNAs (5, 6). Indeed, local protein synthesis affords neurons the ability to stabilize changes in synaptic connections and alter neuronal output (7). Recent studies indicate that cytoplasmic polyadenylation element binding protein 1 (CPEB1) is among a handful of RNA binding proteins that regulate dendritic protein synthesis and synaptic plasticity in vitro (8). Although studies in mutant mice implicate CPEB1 in some forms of synaptic and spine plasticity and in memory extinction (9-11), no studies have examined the potential role of CPEB1 in dendritic arbor development, experience-dependent structural plasticity, or the integration of neurons into a functional circuit in an intact animal.CPEB1 (Orb in D. melanogaster) is a member of an evolutionarily conserved family of RNA binding proteins that is expressed in the brain (in vertebrates, CPEB1-4). While all members are defined by the presence of RNA recognition motifs in their carboxy-terminals, CPEB1 is the only member that targets mRNAs containing cytoplasmic polyadenylation elements (CPEs) in their 3Ј untranslated regions (12). Origina...

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“…We previously identified a possible PEST (proline-, glutamate-, aspartate-, serine-, and threonine-rich) se- quence between 171 and 196 [17]. PEST sequences have been shown to be proteolysis signals in many proteins [29][30][31]. To test whether this PEST motif targets the KLF5 protein for degradation, we generated two KLF5 C-terminus truncated mutants KLF5(1-237) and KLF5(1-171)-His.…”

Section: 2mentioning

confidence: 99%

Proteasomal degradation of the KLF5 transcription factor through a ubiquitin‐independent pathway

et al. 2007

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KLF5 is a Kruppel-like zinc finger transcription factor modulating cell proliferation, differentiation, cell cycle, apoptosis, and angiogenesis. The KLF5 protein undergoes multiple posttranslational modifications including phosphorylation, acetylation and ubiquitination. We have demonstrated that the KLF5 protein can be ubiquitinated by the WWP1 E3 ubiquitin ligase and degraded by the proteasome. In this study, we found that KLF5 protein degradation is blocked by an N-terminal FLAG tag or a small N-terminal deletion without reducing ubiquitination and degradation mediated by WWP1. Interestingly, the N-terminal fragments of KLF5 containing the first 237 or 171 amino acids are as unstable as the full length KLF5 protein.The N-terminal FLAG tag or 19 amino acid deletion also delayed the degradation of the C-terminal truncated KLF5 proteins. To further understand the mechanism, we generated a lysine-less mutant KLF5(1-171). This mutant is efficiently degraded by the proteasome without ubiquitination in vitro and in vivo. These findings suggest that KLF5 protein degradation by the proteasome could be regulated in a ubiquitin-independent manner.

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CPEB Degradation during Xenopus Oocyte Maturation Requires a PEST Domain and the 26S Proteasome

Cited by 84 publications

References 57 publications

Ionizing Radiation Induces Cellular Senescence of Articular Chondrocytes via Negative Regulation of SIRT1 by p38 Kinase

Ionizing Radiation Induces Cellular Senescence of Articular Chondrocytes via Negative Regulation of SIRT1 by p38 Kinase

The RNA binding protein CPEB regulates dendrite morphogenesis and neuronal circuit assembly in vivo

Proteasomal degradation of the KLF5 transcription factor through a ubiquitin‐independent pathway

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