title: The oncoprotein I-2PP2A/SET negatively regulates the MEK/ERK pathway and cell proliferation.
abstract: 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.
authors.affiliation: Division of Biochemical Oncology and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Fukukawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shima
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanuma
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okada
authors.forename: Natsue
authors.initials: N
authors.lastname: Kato
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Adachi
authors.forename: Kunimi
authors.initials: K
authors.lastname: Kikuchi
mesh_terms: 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*
chemical_list: 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