Dataset Information

CPEB1 regulates beta-catenin mRNA translation and cell migration in astrocytes.

ABSTRACT: A crucial step in directed cell migration is the recruitment of cytoskeletal regulatory and signaling proteins to the leading edge of the cell. One protein localized to the leading edge of a migrating astrocyte is beta-catenin. Using an in vitro wound-healing assay, we show that the localization of beta-catenin to the leading edge is dependent upon new protein synthesis at the time of wounding. We examined the mRNA encoding beta-catenin for potential regulatory elements and identified a conserved cytoplasmic polyadenylation element in the 3'-untranslated region (UTR). We now show that the CPE-binding protein (CPEB1) is expressed in astrocytes and that translation of beta-catenin mRNA is regulated by CPEB1. Further, expression of a mutant CPEB1 protein in astrocytes not only blocks beta-catenin protein localization, it also inhibits cell migration. These findings demonstrate a role for CPEB1-mediated protein synthesis in the localization of beta-catenin protein to the leading edge of migrating astrocytes and in regulating directed cell motility.

SUBMITTER: Jones KJ

PROVIDER: S-EPMC3013359 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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CPEB1 regulates beta-catenin mRNA translation and cell migration in astrocytes.

Jones Kendrick J KJ Korb Erica E Kundel Mitchell A MA Kochanek Ashley R AR Kabraji Sheheryar S McEvoy Michael M Shin Chan Y CY Wells David G DG

Glia 20081001 13

A crucial step in directed cell migration is the recruitment of cytoskeletal regulatory and signaling proteins to the leading edge of the cell. One protein localized to the leading edge of a migrating astrocyte is beta-catenin. Using an in vitro wound-healing assay, we show that the localization of beta-catenin to the leading edge is dependent upon new protein synthesis at the time of wounding. We examined the mRNA encoding beta-catenin for potential regulatory elements and identified a conserve ...[more]

PMID: 18618654

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Project description:Reactive astrogliosis is prominent in most neurodegenerative disorders and is often associated with neuroinflammation. The molecular mechanisms regulating astrocyte-linked neuropathogenesis during injury, aging and human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are not fully understood. In this study, we investigated the implications of the wingless type (Wnt)/β-catenin signaling pathway in regulating astrocyte function during gliosis. First, we identified that HIV-associated inflammatory cytokines, interleukin (IL)-1β and tumor necrosis factor (TNF)-α induced mediators of the Wnt/β-catenin pathway including β-catenin and lymphoid enhancer-binding factor (LEF)-1 expression in astrocytes. Next, we investigated the regulatory role of β-catenin on primary aspects of reactive astrogliosis, including proliferation, migration and proinflammatory responses, such as IL-6. Knockdown of β-catenin impaired astrocyte proliferation and migration as shown by reduced cyclin-D1 levels, bromodeoxyuridine incorporation and wound healing. HIV-associated cytokines, IL-1β alone and in combination with TNF-α, strongly induced the expression of proinflammatory cytokines including C-C motif chemokine ligand (CCL)2, C-X-C motif chemokine ligand (CXCL)8 and IL-6; however, only IL-6 levels were regulated by β-catenin as demonstrated by knockdown and pharmacological stabilization. In this context, IL-6 levels were negatively regulated by β-catenin. To better understand this relationship, we examined the crossroads between β-catenin and nuclear factor (NF)-κB pathways. While NF-κB expression was significantly increased by IL-1β and TNF-α, NF-κB levels were not affected by β-catenin knockdown. IL-1β treatment significantly increased glycogen synthase kinase (GSK)-3β phosphorylation, which inhibits β-catenin degradation. Further, pharmacological inhibition of GSK-3β increased nuclear translocation of both β-catenin and NF-κB p65 into the nucleus in the absence of any other inflammatory stimuli. HIV+ human astrocytes show increased IL-6, β-catenin and NF-κB expression levels and are interconnected by regulatory associations during HAND. In summary, our study demonstrates that HIV-associated inflammation increases β-catenin pathway mediators to augment activated astrocyte responses including migration and proliferation, while mitigating IL-6 expression. These findings suggest that β-catenin plays an anti-inflammatory role in activated human astrocytes during neuroinflammatory pathologies, such as HAND.

Dataset Information

CPEB1 regulates beta-catenin mRNA translation and cell migration in astrocytes.

Publications

CPEB1 regulates beta-catenin mRNA translation and cell migration in astrocytes.

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