The oncoprotein I-2PP2A/SET negatively regulates the MEK/ERK pathway and cell proliferation.
I-2PP2A/SET, the translocation breakpoint-encoded protein expressed in acute undifferentiated leukemia, was identified as an inhibitor of protein phosphatase 2A (PP2A). Induction of exogenous I-2PP2A/SET at a ratio of 1:1 to the endogenous protein resulted in suppression of cell proliferation. In contrast, siRNA-mediated depletion of I-2PP2A/SET resulted in enhanced cell proliferation. Depletion of I-2PP2A/SET was accompanied with a decrease in the number of cells in G1 and an increase in cells in S phase. To examine the mode of action by which I-2PP2A/SET suppresses cell proliferation, we determined the effect of over-expressed I-2PP2A/SET on ERK activation. I-2PP2A/SET suppressed activation of ERK following EGF stimulation but did not affect activation levels of stress kinases, JNK and p38. By contrast, knocking down I-2PP2A/SET by siRNA resulted in enhancement of ERK and MEK activations, suggesting that I-2PP2A/SET negatively regulates MEK/ERK. These data suggest that I-2PP2A/SET negatively regulates cell growth by inhibiting the G1/S transition and inhibiting the MEK/ERK pathway stimulated by external stimuli. These data demonstrate that I-2PP2A/SET potentially functions as a tumor suppressor.
Fukukawa
Chikako
C
Division of Biochemical Oncology and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Shima
Hiroshi
H
Tanuma
Nobuhiro
N
Okada
Tadashi
T
Kato
Natsue
N
Adachi
Yoshifumi
Y
Kikuchi
Kunimi
K
D002453:Cell Cycle; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006367:HeLa Cells; D056488:Histone Chaperones; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000494:pharmacology*; D054648:Protein Phosphatase 2; D014157:Transcription Factors / Q000235:genetics* / Q000494:pharmacology*
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C513473:SET protein, human; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2