Phosphorylation of MCT-1 by p44/42 MAPK is required for its stabilization in response to DNA damage.
We discovered a novel oncogene in a T-cell lymphoma cell line, multiple copies in T-cell lymphoma-1 (MCT-1), that has been shown to decrease cell-doubling time, shorten the duration of G(1) transit time and/or G(1)-S transition, and transform NIH3T3 fibroblasts. We subsequently demonstrated that there were significantly increased levels of MCT-1 protein in a subset of primary diffuse large B-cell lymphomas. Levels of MCT-1 protein were shown to be increased after exposure to DNA damaging agents. This increase did not require new protein synthesis, suggesting that post-translational mechanisms were involved. Phosphorylation is one potential mechanism by which the activity of molecules involved in cell cycle/survival is rapidly modulated. The RAS/mitogen-activated/extracellular-regulated kinase (MEK)/extracellular signal-regulated kinases (ERK) pathway plays a prominent role in the regulation of cell growth and proliferation through phosphorylation-dependent regulation of several substrates. The MCT-1 protein is predicted to have numerous putative phosphorylation sites. Using a combination of genetic and pharmacological approaches, we established that phosphorylation of MCT-1 protein by p44/p42 mitogen-activated protein kinases is critical for stabilization of MCT-1 protein and for its ability to promote cell proliferation. Our data suggests that targeting the RAS/MEK/ERK signal transduction cascade may provide a potential therapeutic approach in lymphomas and related malignancies that exhibit high levels of MCT-1 protein.
Nandi
S
S
Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
Reinert
L S
LS
Hachem
A
A
Mazan-Mamczarz
K
K
Hagner
P
P
He
H
H
Gartenhaus
R B
RB
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D004249:DNA Damage; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000473:pathology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation
D018797:Cell Cycle Proteins; C115081:MCTS1 protein, human; D015513:Oncogene Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3