Association between LRRK2 and 4E-BP1 protein levels in normal and malignant cells
Pons López, Berta (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Armengol Rosell, Gemma (Universitat Autònoma de Barcelona. Departament de Biologia Animal, de Biologia Vegetal i d'Ecologia)
Livingstone, Mark (McGill University. Department of Biochemistry)
López, Laura (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Coch, Laura (Hospital Universitari Vall d'Hebron. Servei de Patologia)
Sonenberg, Nahum (McGill University. Department of Biochemistry)
Ramón y Cajal, Santiago (Hospital Universitari Vall d'Hebron. Servei de Patologia)

Date:	2012
Abstract:	Translational control is a crucial component of cancer development and progression. Eukaryotic initiation factor (eIF) 4E mediates eIF4F association with the mRNA 5' cap structure to stimulate cap-dependent translation initiation. The eIF4E-binding protein, 4E-BP1, regulates cap-dependent translation through its phosphorylation at multiple sites. It has been described that some human carcinomas present a high level of p-4E-BP1, not always associated with high levels of p-mTOR. These previous observations suggest that other kinases could be involved in 4E-BP1 phosporylation. Investigation in new kinases that could be implicated in 4E-BP1 phosphorylation and mechanisms that affect 4E-BP1 stability is important to understand the role of eIF4E in cell transformation. In this study, we examined 48 kinases that could be involved in 4E-BP1 phosphorylation and stability. The screening study was based on analysis of 4E-BP1 status after inhibition of these kinases in a breast carcinoma cell line. Several kinases affecting 4E-BP1 stability (LRRK2, RAF-1, p38γ, GSK3β, AMPKα, PRKACA and PRKACB) and 4E-BP1 phosphorylation (CDK1, PDK1, SRC, PRKCB1, PAK2, p38β, PRKCA and CaMKKB) were identified. These findings provide evidence that 4E-BP1 can be regulated and stabilized by multiple kinases implicated in several cell signaling pathways. We focus on the finding that LRRK2 down-regulation was associated with a clearly decreased 4E-BP1 protein (and not with mRNA down-regulation). Importantly, knockdown of LRRK2 associated with high proliferative rate in normal cells and treatment with rapamycin and/or proteosome inhibition suppressed 4E-BP1 protein degradation. These results offer new insights into the regulation of total and phosphorylated 4E-BP1.
Grants:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2005/SGR-00144 Fundació la Marató de TV3 052710
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Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	4E-BP1 ; Kinases ; LRRK2 ; MG132 ; Proteasome ; Protein degradation ; SDG 3 - Good Health and Well-being
Published in:	Oncology Reports, Vol. 27, issue 1 (January 2012) , p. 225-231, ISSN 1791-2431

DOI: 10.3892/or.2011.1462

7 p, 477.7 KB

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