期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 276, 期 31, 页码 29531-29537出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M100069200
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资金
- NCI NIH HHS [CA69457, CA68485, CA77839] Funding Source: Medline
- NIDDK NIH HHS [DK52334, F32 DK10138] Funding Source: Medline
The loss of growth-inhibitory responses to transforming growth factor-beta (TGF-beta) is a frequent consequence of malignant transformation. Smad2, Smad3, and Smad4 proteins are important mediators of the antiproliferative responses to TGF-beta and may become inactivated in some human cancers. Epithelial cells harboring oncogenic Ras mutations often exhibit a loss of TGF-beta antiproliferative responses. To further investigate the effect of oncogenic Ras in TGF-beta signaling, we used an isopropyl-1-thio-beta -D-galactopyranoside-inducible expression system to express Ha-Ras (Val-12) in intestinal epithelial cells. Induction of Ha-Ras(Val-12) caused a decrease in the level of Smad4 expression, inhibited TGF-beta -induced complex formation between Smad2/Smad3 and Smad4, blocked Smad4 nuclear translocation, inhibited the TGF-beta -mediated decrease in [H-3]thymidine incorporation, and repressed TGF-beta -activated transcriptional responses. The withdrawal of isopropyl-1-thio-beta -D-galactopyranoside or the addition of an inhibitor of the ubiquitin-proteasome pathway restored the Smad4 level and TGF-beta -induced Smad complex formation. Forced expression of Smad4 resulted in partial recovery of the TGF-beta -mediated growth inhibition and transcriptional responses in the presence of oncogenic Ras. Further, PD98059, a specific inhibitor of the MEK/ERF/mitogenactivated protein kinase pathway prevented the Ras-induced decrease in Smad4 expression and complex formation. Our results suggest a novel mechanism by which oncogenic Ras represses TGF-beta signaling by mitogen-activated protein kinase-dependent down-regulation of Smad4, thereby subverting the tumor suppressor function of TGF-beta.
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