SnoN is a cell type-specific mediator of transforming growth factor-beta responses.
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.
Sarker
Krishna P
KP
Cancer Biology Research Group and Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Wilson
Sylvia M
SM
Bonni
Shirin
S
D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000166:cytology* / Q000378:metabolism; D008907:Mink; D008969:Molecular Sequence Data; D010957:Plasmids / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; C060615:SKIL protein, human; D051785:Smad Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D012313:RNA; D008156:Luciferases