Abstract
The transforming growth factor-beta (TGF-beta) family of secreted proteins have pleiotropic functions that are critical to normal development and homeostasis. However, the intracellular mechanisms by which the TGF-beta proteins elicit cellular responses remain incompletely understood. The Smad proteins provide a major means for the propagation of the TGF-beta signal from the cell surface to the nucleus, where the Smad proteins regulate gene expression leading to TGF-beta-dependent cellular responses including the inhibition of cell proliferation. Recent studies have suggested that a nuclear Smad-interacting protein termed SnoN, when overexpressed in cells, suppresses TGF-beta-induced Smad signaling and TGF-beta inhibition of cell proliferation. However, the physiologic function of endogenous SnoN in TGF-beta-mediated biological responses remained to be elucidated. Here, we determined the effect of genetic knock-down of SnoN by RNA interference on TGF-beta responses in mammalian cells. Unexpectedly, we found that SnoN knock-down specifically inhibited TGF-beta-induced transcription in the lung epithelial cell line Mv1Lu but not in HeLa or HaCaT cells. SnoN knock-down was also found to block TGF-beta-dependent cell cycle arrest in Mv1Lu cells. Collectively, these data indicate that rather than suppressing TGF-beta-induced responses, endogenous SnoN acts as a positive mediator of TGF-beta-induced transcription and cell cycle arrest in lung epithelial cells. Our study also shows that SnoN couples the TGF-beta signal to gene expression in a cell-specific manner.
Highlights
The transforming growth factor- (TGF-)1 superfamily of growth factors comprises a large family cytokines that includes the TGF-, activins, and the bone morphogenetic proteins [1, 2]
The Smad proteins provide a major means for the propagation of the TGF- signal from the cell surface to the nucleus, where the Smad proteins regulate gene expression leading to TGF--dependent cellular responses including the inhibition of cell proliferation
Knock-down of SnoN by RNA Interference—The finding that SnoN is ubiquitinated by the TGF--induced Smad2/3-Smurf2 or Smad2/3-Cdh1-anaphase-promoting complex ubiquitin ligase complexes suggests that SnoN is an important target of TGF--induced signaling
Summary
The TGF-1 superfamily of growth factors comprises a large family cytokines that includes the TGF-, activins, and the bone morphogenetic proteins [1, 2]. We found that SnoN knock-down inhibited TGF--induced transcription in the lung epithelial cell line Mv1Lu but not in HeLa or HaCaT cells. These data indicate that endogenous SnoN acts in a cell type-specific manner to mediate TGF- transcriptional responses and thereby contributes to TGF--dependent inhibition of proliferation in epithelial cells.
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