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: Chikako Fukukawa, Hiroshi Shima, Nobuhiro Tanuma, Tadashi Okada, Natsue Kato, Yoshifumi Adachi, Kunimi Kikuchi
• Journal: International journal of oncology (Int J Oncol) Vol. 26 Issue 3 Pg. 751-6 (Mar 2005) ISSN: 1019-6439 [Print] Greece
• PMID: 15703833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromosomal Proteins, Non-Histone
• DNA-Binding Proteins
• Histone Chaperones
• SET protein, human
• Transcription Factors
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase Kinases
• Phosphoprotein Phosphatases
• Protein Phosphatase 2

Topics

• Cell Cycle
• Cell Proliferation
• Chromosomal Proteins, Non-Histone (genetics, pharmacology)
• DNA-Binding Proteins
• Extracellular Signal-Regulated MAP Kinases (pharmacology)
• Gene Expression Profiling
• HeLa Cells
• Histone Chaperones
• Humans
• MAP Kinase Kinase Kinases (pharmacology)
• Phosphoprotein Phosphatases (genetics, pharmacology)
• Protein Phosphatase 2
• Transcription Factors (genetics, pharmacology)