This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, M. Articles by Cowan, K. H. Search for Related Content PubMed PubMed Citation Articles by Kim, M. Articles by Cowan, K. H.

Expression of Kinase Suppressor of Ras1 Enhances Cisplatin-Induced Extracellular Signal–Regulated Kinase Activation and Cisplatin Sensitivity

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska

Requests for reprints: Kenneth H. Cowan, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805. Phone: 402-559-4238; Fax: 402-559-4651; E-mail: kcowan{at}unmc.edu.

Kinase suppressor of Ras1 (KSR1) interacts with several mitogen-activated protein (MAP) kinase pathway components, including Raf, MAP/extracellular signal–regulated kinase (ERK) kinase (MEK), and ERK, and acts as a positive regulator of the Ras signaling cascade. Previous studies have shown that exposure of cells to the anticancer agent cisplatin (cis-diamminedichloroplatinum, CDDP) is associated with changes in multiple signal transduction pathways, including c-Jun-NH₂-kinase, ERK, and p38 pathways. Moreover, ERK activation has been linked to changes in cell survival following CDDP treatment. In this report, we have examined the effects of KSR1 expression on the sensitivity of cells to CDDP-induced apoptosis. Loss of KSR1 expression in mouse embryo fibroblasts (MEFs) derived from KSR1 knockout mice (KSR^–/– MEF) is associated with decreased CDDP-induced ERK activation and increased resistance to CDDP-induced apoptosis compared with wild-type MEFs (KSR^+/+ MEF). Furthermore, transduction of KSR^–/– MEFs and MCF-7 breast cancer cells with wild-type KSR1 resulted in enhanced ERK activation following CDDP exposure and increased sensitivity to CDDP. In addition, inhibition of ERK activation by exposing MEFs to the MEK1/2-specific inhibitors PD98059 and U0126 protected both KSR^+/+ and KSR^–/– MEFs cells from CDDP-induced apoptosis. These results indicate that KSR1-mediated regulation of ERK activity represents a novel determinant of CDDP sensitivity of cancer cells.

This article has been cited by other articles:

				G. L. Razidlo, H. J. Johnson, S. M. Stoeger, K. H. Cowan, T. Bessho, and R. E. Lewis KSR1 Is Required for Cell Cycle Reinitiation Following DNA Damage J. Biol. Chem., March 13, 2009; 284(11): 6705 - 6715. [Abstract] [Full Text] [PDF]

				X. Wang, R. Patel, and G. P. Studzinski hKSR-2, a vitamin D-regulated gene, inhibits apoptosis in arabinocytosine-treated HL60 leukemia cells Mol. Cancer Ther., September 1, 2008; 7(9): 2798 - 2806. [Abstract] [Full Text] [PDF]