NDLI: Down-regulation of the Tumor Suppressor C-terminal Src Kinase (Csk)-binding Protein (Cbp)/PAG1 Is Mediated by Epigenetic Histone Modifications via the Mitogen-activated Protein Kinase (MAPK)/Phosphatidylinositol 3-Kinase (PI3K) Pathway*

Content Provider	PubMed Central
Author	Suzuki, Kei Oneyama, Chitose Kimura, Hironobu Tajima, Shoji Okada, Masato
Copyright Year	2011
Abstract	The transmembrane adaptor protein Cbp (or PAG1) functions as a suppressor of Src-mediated tumor progression by promoting the inactivation of Src. The expression of Cbp is down-regulated in Src-transformed cells and in various human cancer cells, suggesting a potential role for Cbp as a tumor suppressor. However, the mechanisms underlying the down-regulation of Cbp remain unknown. The present study shows that Cbp expression is down-regulated by epigenetic histone modifications via the MAPK/PI3K pathway. In mouse embryonic fibroblasts, transformation by oncogenic Src and Ras induced a marked down-regulation of Cbp expression. The levels of Cbp expression were inversely correlated with the activity of MEK and Akt, and Cbp down-regulation was suppressed by inhibiting MEK and PI3K. Src transformation did not affect the stability of Cbp mRNA, the transcriptional activity of the cbp promoter, or the DNA methylation status of the cbp promoter CpG islands. However, Cbp expression was restored by treatment with histone deacetylase (HDAC) inhibitors and by siRNA-mediated knockdown of HDAC1/2. Src transformation significantly decreased the acetylation levels of histone H4 and increased the trimethylation levels of histone H3 lysine 27 in the cbp promoter. EGF-induced Cbp down-regulation was also suppressed by inhibiting MEK and HDAC. Furthermore, the inhibition of MEK or HDAC restored Cbp expression in human cancer cells harboring Cbp down-regulation through promoter hypomethylation. These findings suggest that Cbp down-regulation is primarily mediated by epigenetic histone modifications via oncogenic MAPK/PI3K pathways in a subset of cancer cells.
Related Links	http://dx.doi.org/10.1074/jbc.m110.195362
Ending Page	15706
Page Count	9
Starting Page	15698
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	18
Volume Number	286
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2011-05-06
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Down-regulation of the Tumor Suppressor C-terminal Src Kinase (Csk)-binding Protein (Cbp)/PAG1 Is Mediated by Epigenetic Histone Modifications via the Mitogen-activated Protein Kinase (MAPK)/Phosphatidylinositol 3-Kinase (PI3K) Pathway

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Down-regulation of the Tumor Suppressor C-terminal Src Kinase (Csk)-binding Protein (Cbp)/PAG1 Is Mediated by Epigenetic Histone Modifications via the Mitogen-activated Protein Kinase (MAPK)/Phosphatidylinositol 3-Kinase (PI3K) Pathway*

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