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Vol. 16, Issue 10, 4672-4683, October 2005

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The Endogenous Ratio of Smad2 and Smad3 Influences the Cytostatic Function of Smad3

Sang Gyun Kim ^*, Hyun-Ah Kim ^*, Hyun-Soon Jong ^*, Jung-Hyun Park ^*, Noe Kyeong Kim , Seung Hwan Hong , Tae-You Kim ^* , and Yung-Jue Bang ^* 

^* National Research Laboratory for Cancer Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea; and School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea

Submitted January 20, 2005; Revised August 1, 2005; Accepted August 2, 2005
Monitoring Editor: Carl-Henrik Heldin

Although Smad2 and Smad3, critical transcriptional mediators of transforming growth factor- (TGF-) signaling, are supposed to play a role in the TGF- cytostatic program, it remains unclear whether TGF- delivers cytostatic signals through both Smads equally or through either differentially. Here, we report that TGF- cytostatic signals rely on a Smad3-, but not a Smad2-, dependent pathway and that the intensity of TGF- cytostatic signals can be modulated by changing the endogenous ratio of Smad3 to Smad2. Depleting endogenous Smad3 by RNA interference sufficiently interfered with TGF- cytostatic actions in various TGF--sensitive cell lines, whereas raising the relative endogenous ratio of Smad3 to Smad2, by depleting Smad2, markedly enhanced TGF- cytostatic response. Consistently, Smad3 activation and its transcriptional activity upon TGF- stimulation were facilitated in Smad2-depleted cells relative to controls. Most significantly, a single event of increasing this ratio by Smad2 depletion was sufficient to restore TGF- cytostatic action in cells resistant to TGF-. These findings suggest a new important determinant of sensitivity to TGF- cytostatic signaling.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Yung-Jue Bang (bangyj{at}plaza.snu.ac.kr).

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