Association between LRRK2 and 4E-BP1 protein levels in normal and malignant cells

  • Authors:
    • Berta Pons
    • Gemma Armengol
    • Mark Livingstone
    • Laura López
    • Laura Coch
    • Nahum Sonenberg
    • Santiago Ramón y Cajal
  • View Affiliations

  • Published online on: September 14, 2011     https://doi.org/10.3892/or.2011.1462
  • Pages: 225-231
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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.

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January 2012
Volume 27 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Pons B, Armengol G, Livingstone M, López L, Coch L, Sonenberg N and Ramón y Cajal S: Association between LRRK2 and 4E-BP1 protein levels in normal and malignant cells. Oncol Rep 27: 225-231, 2012.
APA
Pons, B., Armengol, G., Livingstone, M., López, L., Coch, L., Sonenberg, N., & Ramón y Cajal, S. (2012). Association between LRRK2 and 4E-BP1 protein levels in normal and malignant cells. Oncology Reports, 27, 225-231. https://doi.org/10.3892/or.2011.1462
MLA
Pons, B., Armengol, G., Livingstone, M., López, L., Coch, L., Sonenberg, N., Ramón y Cajal, S."Association between LRRK2 and 4E-BP1 protein levels in normal and malignant cells". Oncology Reports 27.1 (2012): 225-231.
Chicago
Pons, B., Armengol, G., Livingstone, M., López, L., Coch, L., Sonenberg, N., Ramón y Cajal, S."Association between LRRK2 and 4E-BP1 protein levels in normal and malignant cells". Oncology Reports 27, no. 1 (2012): 225-231. https://doi.org/10.3892/or.2011.1462