Cytoplasmic SnoN in normal tissues and nonmalignant cells antagonizes TGF-beta signaling by sequestration of the Smad proteins.
TGF-beta is a ubiquitously expressed cytokine that signals through the Smad proteins to regulate many diverse cellular processes. SnoN is an important negative regulator of Smad signaling. It has been described as a nuclear protein, based on studies of ectopically expressed SnoN and endogenous SnoN in cancer cell lines. In the nucleus, SnoN binds to Smad2, Smad3, and Smad4 and represses their ability to activate transcription of TGF-beta target genes through multiple mechanisms. Here, we show that, whereas SnoN is localized exclusively in the nucleus in cancer tissues or cells, in normal tissues and nontumorigenic or primary epithelial cells, SnoN is predominantly cytoplasmic. Upon morphological differentiation or cell-cycle arrest, SnoN translocates into the nucleus. In contrast to nuclear SnoN that represses the transcriptional activity of the Smad complexes, cytoplasmic SnoN antagonizes TGF-beta signaling by sequestering the Smad proteins in the cytoplasm. Interestingly, cytoplasmic SnoN is resistant to TGF-beta-induced degradation and therefore is more potent than nuclear SnoN in repressing TGF-beta signaling. Thus, we have identified a mechanism of regulation of TGF-beta signaling via differential subcellular localization of SnoN that is likely to produce different patterns of downstream TGF-beta responses and may influence the proliferation or differentiation states of epithelial cells.
Krakowski
Ariel R
AR
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Laboureau
Julien
J
Mauviel
Alain
A
Bissell
Mina J
MJ
Luo
Kunxin
K
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019913:Nuclear Localization Signals; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019913:Nuclear Localization Signals; D011518:Proto-Oncogene Proteins; C060615:SKIL protein, human; D051785:Smad Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta