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 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.
Kim
Sang Gyun
SG
National Research Laboratory for Cancer Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, Korea.
Kim
Hyun-Ah
HA
Jong
Hyun-Soon
HS
Park
Jung-Hyun
JH
Kim
Noe Kyeong
NK
Hong
Seung Hwan
SH
Kim
Tae-You
TY
Bang
Yung-Jue
YJ
D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D003593:Cytoplasm / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D008907:Mink; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000502:physiology*; D051900:Smad3 Protein / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D034741:RNA, Small Interfering; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta