Phosphorylation of the MCT-1 Oncogene Protein by p42/44 MAPK Is Required for Transformation.

Abstract

The MCT-1 oncogene has been shown to decrease cell doubling time, dramatically shorten the duration of G1 transit time and/or G1-S transition, as well as transform NIH3T3 fibroblasts. We subsequently demonstrated that there are significantly increased levels of MCT-1 protein in a subset of primary diffuse large B-cell lymphomas (DLBCL) as well as some T-cell lymphomas compared with normal lymphoid tissue. We have mapped MCT-1 to chromosome Xq22-24, a region that has been previously shown to contain amplified DNA in a variety of primary B-cell lymphoid neoplasms using comparative genomic hybridization (CGH). Recent data has shown that MCT-1 is involved in protection against serum-starvation induced apoptosis involving enhanced AKT activity. Phosphorylation is one potential mechanism by which the activity of molecules involved in cell cycle regulation/survival is rapidly modulated. The RAS/MEK/ERK signal transduction cascade plays a prominent role in the regulation of cell growth and proliferation. The MCT-1 protein is predicted to have several putative phosphorylation sites including, a p42/p44 MAPK and cyclinB/cdc2 kinase substrate site. These cdc2 and MAPK phosphorylation sites have been mutated through site-directed mutagenesis and expressed in human dermal fibroblasts (HDF) in order to examine the role of these kinase sites on cell growth and transformation. We demonstrated that the phosphorylation of MCT-1 by p42/p44 MAPK is critical for its ability to stimulate cell proliferation as well as cellular transformation. Our data suggest that targeting the RAS/MEK/ERK signal transduction cascade may be a useful therapeutic approach in those lymphomas and related disorders overexpressing MCT-1.