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Type: Artigo de periódico
Title: Knockdown Of Insulin Receptor Substrate 1 Reduces Proliferation And Downregulates Akt/mtor And Mapk Pathways In K562 Cells.
Author: Machado-Neto, João Agostinho
Favaro, Patricia
Lazarini, Mariana
Costa, Fernando Ferreira
Olalla Saad, Sara T
Traina, Fabiola
Abstract: BCR-ABL kinase activates downstream signaling pathways, including the PI3K-Akt/mTOR and the MAPK pathway. IRS1 has been previously described as constitutively phosphorylated and associated with BCR-ABL in K562 cells, suggesting that IRS1 has role in the BCR-ABL signaling pathways. In this study, we analyzed the effect of IRS1 silencing, by shRNA-lentiviral delivery, in K562 cells, a CML cell line that presents the BCR-ABL. IRS1 silencing decreased cell proliferation and colony formation in K562 cells, which correlates with the delay of these cells at the G0/G1 phase and a decrease in the S phase of the cell cycle. Furthermore, IRS1 silencing in K562 cells resulted in a decrease of Akt, P70S6K and ERK1/2 phosphorylation. Nevertheless, apoptosis was unaffected by IRS1 knockdown and no alterations were found in the phosphorylation of BAD and in the expression of BCL2 and BAX. BCR-ABL and CRKL phosphorylation levels remained unaffected upon IRS1 silencing, and no synergistic effect was observed with imatinib treatment and IRS1 knockdown, indicating that IRS1 is downstream from BCR-ABL. In conclusion, we demonstrated that inhibition of IRS1 is capable of inducing the downregulation of Akt/mTOR and MAPK pathways and further decreasing proliferation, and clonogenicity and induces to cell cycle delay at G0/G1 phase in BCR-ABL cells.
Subject: Adaptor Proteins, Signal Transducing
Base Sequence
Caspase 3
Cell Cycle
Cell Proliferation
Colony-forming Units Assay
Dna Primers
Fusion Proteins, Bcr-abl
Gene Knockdown Techniques
Insulin Receptor Substrate Proteins
K562 Cells
Map Kinase Signaling System
Nuclear Proteins
Proto-oncogene Proteins C-akt
Rna, Small Interfering
Signal Transduction
Tor Serine-threonine Kinases
Citation: Biochimica Et Biophysica Acta. v. 1813, n. 8, p. 1404-11, 2011-Aug.
Rights: fechado
Identifier DOI: 10.1016/j.bbamcr.2011.04.002
Date Issue: 2011
Appears in Collections:Unicamp - Artigos e Outros Documentos

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