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PKC? promotes HuD-mediated neprilysin mRNA stability and enhances neprilysin-induced A? degradation in brain neurons.

ABSTRACT: Amyloid-beta (A?) peptide accumulation in the brain is a pathological hallmark of all forms of Alzheimer's disease. An imbalance between A? production and clearance from the brain may contribute to accumulation of neurotoxic A? and subsequent synaptic loss, which is the strongest correlate of the extent of memory loss in AD. The activity of neprilysin (NEP), a potent A?-degrading enzyme, is decreased in the AD brain. Expression of HuD, an mRNA-binding protein important for synaptogenesis and neuronal plasticity, is also decreased in the AD brain. HuD is regulated by protein kinase C? (PKC?), and we previously demonstrated that PKC? activation decreases A? levels. We hypothesized that PKC? acts through HuD to stabilize NEP mRNA, modulate its localization, and support NEP activity. Conversely, loss of PKC?-activated HuD in AD leads to decreased NEP activity and accumulation of A?. Here we show that HuD is associated with NEP mRNA in cultures of human SK-N-SH cells. Treatment with bryostatin, a PKC?-selective activator, enhanced NEP association with HuD and increased NEP mRNA stability. Activation of PKC? also increased NEP protein levels, increased NEP phosphorylation, and induced cell surface expression. In addition, specific PKC? activation directly stimulated NEP activity, leading to degradation of a monomeric form of A? peptide and decreased A? neuronal toxicity, as measured by cell viability. Bryostatin treatment also rescued A?-mediated inhibition of HuD-NEP mRNA binding, NEP protein expression, and NEP cell membrane translocation. These results suggest that PKC? activation reduces A? by up-regulating, via the mRNA-binding protein HuD, A?-degrading enzymes such as NEP. Thus, PKC? activation may have therapeutic efficacy for AD by reducing neurotoxic A? accumulation as well as having direct anti-apoptotic and synaptogenic effects.

SUBMITTER: Lim CS

PROVIDER: S-EPMC4029802 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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PKCε promotes HuD-mediated neprilysin mRNA stability and enhances neprilysin-induced Aβ degradation in brain neurons.

Lim Chol Seung CS Alkon Daniel L DL

PloS one 20140521 5

Amyloid-beta (Aβ) peptide accumulation in the brain is a pathological hallmark of all forms of Alzheimer's disease. An imbalance between Aβ production and clearance from the brain may contribute to accumulation of neurotoxic Aβ and subsequent synaptic loss, which is the strongest correlate of the extent of memory loss in AD. The activity of neprilysin (NEP), a potent Aβ-degrading enzyme, is decreased in the AD brain. Expression of HuD, an mRNA-binding protein important for synaptogenesis and neu ...[more]

PMID: 24848988

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Project description:BackgroundChemoresistance to cisplatin (DDP) remains a major challenge in advanced gastric cancer (GC) treatment. Although accumulating evidence suggests an association between dysregulation of long non-coding RNAs (lncRNAs) and chemoresistance, the regulatory functions and complexities of lncRNAs in modulating DDP-based chemotherapy in GC remain under-investigated. This study was designed to explore the critical chemoresistance-related lncRNAs in GC and identify novel therapeutic targets for patients with chemoresistant GC.MethodsChemoresistance-related lncRNAs were identified through microarray and verified through a quantitative real-time polymerase chain reaction (qRT-PCR). Proteins bound by lncRNAs were identified through a human proteome array and validated through RNA immunoprecipitation (RIP) and RNA pull-down assays. Co-immunoprecipitation and ubiquitination assays were performed to explore the molecular mechanisms of the Musashi2 (MSI2) post-modification. The effects of LINC00942 (LNC942) and MSI2 on DDP-based chemotherapy were investigated through MTS, apoptosis assays and xenograft tumour formation in vivo.ResultsLNC942 was found to be up-regulated in chemoresistant GC cells, and its high expression was positively correlated with the poor prognosis of patients with GC. Functional studies indicated that LNC942 confers chemoresistance to GC cells by impairing apoptosis and inducing stemness. Mechanically, LNC942 up-regulated the MSI2 expression by preventing its interaction with SCFβ-TRCP E3 ubiquitin ligase, eventually inhibiting ubiquitination. Then, LNC942 stabilized c-Myc mRNA in an N6-methyladenosine (m6 A)-dependent manner. As a potential m6 A recognition protein, MSI2 stabilized c-Myc mRNA with m6 A modifications. Moreover, inhibition of the LNC942-MSI2-c-Myc axis was found to restore chemosensitivity both in vitro and in vivo.ConclusionsThese results uncover a chemoresistant accelerating function of LNC942 in GC, and disrupting the LNC942-MSI2-c-Myc axis could be a novel therapeutic strategy for GC patients undergoing chemoresistance.

Dataset Information

PKC? promotes HuD-mediated neprilysin mRNA stability and enhances neprilysin-induced A? degradation in brain neurons.

Publications

PKCε promotes HuD-mediated neprilysin mRNA stability and enhances neprilysin-induced Aβ degradation in brain neurons.

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