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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

A Cyclin D2-derived peptide acts on specific cell cycle phases by activating ERK1/2 to cause the death of breast cancer cells

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Russo, Lilian C. ; Araujo, Christiane B. ; Iwai, Leo K. ; Ferro, Emer S. ; Forti, Fabio L.
Número total de Autores: 5
Tipo de documento: Artigo Científico
Fonte: JOURNAL OF PROTEOMICS; v. 151, n. SI, p. 24-32, JAN 16 2017.
Citações Web of Science: 7

Protein degradation by the proteasome generates functional intracellular peptides. Pep5, a peptide derived from Cyclin D2, induces cell death in tumor cell lines and reduces the volume of rat C6 glioblastoma tumors in vivo. Here, we chose the human MDA-MB-231 breast cancer cells to evaluate the mechanism of cell death induced by pep5 in different phases of the cell cycle. Fluorescently labeled pep5, monitored by real time confocal microscopy, entered the MDA-MB-231 cells 3 min after application and localized to the nucleus and cytoplasm. Pep5-induced cell death was increased when the MDA-MB-231 cell population was arrested at the G1/S transition or in S phase compared to asynchronous cells. Pep5 induced permanent extracellular signal-regulated kinase (ERK1/2) phosphorylation in MDA-MB-231 cells synchronized in G1/S or S phase. Affinity chromatography followed by mass spectrometry identified CLIC1 and Plectin as the only two proteins that interacted with pep5 in both asynchronous and synchronized MDA-MB-231 cells. These interactions could explain the long-lasting ERK1/2 phosphorylation and the cytoskeleton perturbations in the MDA-MB-231 cells, in which the stress fibers' integrity is affected by pep5 treatments. These data suggest that pep5 has potential therapeutic properties for treating specific types of cancers, such as breast cancer cells. Biological significance: Pep5, a natural intracellular peptide formed by the degradation of Cyclin D2 through the ubiquitin proteasome system, induces cell death when reintroduced into MDA-MB-231 breast cancer cells, which express low levels of Cyclin D2, specifically in G1/S arrested cells or in cells that are passing through S phase. Under these conditions, pep5 is able to interact with different intracellular proteins, primarily cytoskeleton and proteasome components, which can lead to cellular apoptosis. Together, our data suggest that pep5 is an intracellular peptide with therapeutic potential for treating specific types of tumors with low expression of Cyclin D2 by inhibiting cell proliferation. (C) 2016 Elsevier B.V. All rights reserved. (AU)

Processo FAPESP: 13/07467-1 - CeTICS - Centro de Toxinas, Imuno-Resposta e Sinalização Celular
Beneficiário:Hugo Aguirre Armelin
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 08/58264-5 - Papel de GTPases da família Rho e de tirosina fosfatases duais no reparo de danos no DNA
Beneficiário:Fábio Luis Forti
Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores
Processo FAPESP: 15/03983-0 - Investigação molecular e funcional da interação de DUSP3 com proteínas nucleares: implicações em mecanismos de reparo de DNA
Beneficiário:Fábio Luis Forti
Linha de fomento: Auxílio à Pesquisa - Regular