Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Kim SG

PROVIDER: S-EPMC1237073 | biostudies-literature | 2005 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Kim Sang Gyun SG 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

Molecular biology of the cell 20050810 10

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 end ...[more]

PMID: 16093355

Similar Datasets

Project description:TGFβs act through canonical and non-canonical pathways, and canonical signals are transduced via Smad2 and Smad3. However, the contribution of canonical vs. non-canonical pathways in cartilage is unknown because the role of Smad2 in chondrogenesis has not been investigated in vivo. Therefore, we analyzed mice in which Smad2 is deleted in cartilage (Smad2CKO), global Smad3-/- mutants, and crosses of these strains. Growth plates at birth from all mutant strains exhibited expanded columnar and hypertrophic zones, linked to increased proliferation in resting chondrocytes. Defects were more severe in Smad2CKO and Smad2CKO;Smad3-/- (Smad2/3) mutant mice than in Smad3-/- mice, demonstrating that Smad2 plays a role in chondrogenesis. Increased levels of Ihh RNA, a key regulator of chondrocyte proliferation and differentiation, were seen in prehypertrophic chondrocytes in the three mutant strains at birth. In accordance, TGFβ treatment decreased Ihh RNA levels in primary chondrocytes from control (Smad2fx/fx) mice, but inhibition was impaired in cells from mutants. Consistent with the skeletal phenotype, the impact on TGFβ-mediated inhibition of Ihh RNA expression was more severe in Smad2CKO than in Smad3-/- cells. Putative Smad2/3 binding elements (SBEs) were identified in the proximal Ihh promoter. Mutagenesis demonstrated a role for three of them. ChIP analysis suggested that Smad2 and Smad3 have different affinities for these SBEs, and that the repressors SnoN and Ski were differentially recruited by Smad2 and Smad3, respectively. Furthermore, nuclear localization of the repressor Hdac4 was decreased in growth plates of Smad2CKO and double mutant mice. TGFβ induced association of Hdac4 with Smad2, but not with Smad3, on the Ihh promoter. Overall, these studies revealed that Smad2 plays an essential role in the development of the growth plate, that both Smads 2 and 3 inhibit Ihh expression in the neonatal growth plate, and suggested they accomplish this by binding to distinct SBEs, mediating assembly of distinct repressive complexes.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets