The endogenous ratio of Smad2 and Smad3 influences the cytostatic function of Smad3

Although Smad2 and Smad3, critical transcriptional mediators of transforming growth factor-beta (TGF-beta) signaling, are supposed to play a role in the TGF-beta cytostatic program, it remains unclear whether TGF-beta delivers cytostatic signals through both Smads equally or through either different...

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Published inMolecular biology of the cell Vol. 16; no. 10; pp. 4672 - 4683
Main Authors Kim, Sang Gyun, Kim, Hyun-Ah, Jong, Hyun-Soon, Park, Jung-Hyun, Kim, Noe Kyeong, Hong, Seung Hwan, Kim, Tae-You, Bang, Yung-Jue
Format Journal Article
LanguageEnglish
Published United States 01.10.2005
Subjects
Animals
Cell Cycle
Cell Line
Cell Proliferation
Cytoplasm - physiology
Epithelial Cells - physiology
Gene Expression Regulation
Genes, Reporter
Humans
Mink
RNA, Small Interfering - genetics
Signal Transduction
Smad2 Protein - genetics
Smad2 Protein - physiology
Smad3 Protein - genetics
Smad3 Protein - physiology
Transforming Growth Factor beta - physiology
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Summary:Although Smad2 and Smad3, critical transcriptional mediators of transforming growth factor-beta (TGF-beta) signaling, are supposed to play a role in the TGF-beta cytostatic program, it remains unclear whether TGF-beta delivers cytostatic signals through both Smads equally or through either differentially. Here, we report that TGF-beta cytostatic signals rely on a Smad3-, but not a Smad2-, dependent pathway and that the intensity of TGF-beta cytostatic signals can be modulated by changing the endogenous ratio of Smad3 to Smad2. Depleting endogenous Smad3 by RNA interference sufficiently interfered with TGF-beta cytostatic actions in various TGF-beta-sensitive cell lines, whereas raising the relative endogenous ratio of Smad3 to Smad2, by depleting Smad2, markedly enhanced TGF-beta cytostatic response. Consistently, Smad3 activation and its transcriptional activity upon TGF-beta 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-beta cytostatic action in cells resistant to TGF-beta. These findings suggest a new important determinant of sensitivity to TGF-beta cytostatic signaling.
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ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E05-01-0054