SnoN co-repressor binds and represses smad7 gene promoter

Smad7 inhibits autocrine expression of TGF-β2in intestinal epithelial cells in baboon necrotizing enterocolitis

“…Deficiency of SKI and/or SnoN/SKIL could potentially explain increased Smad7 and decreased TGF-␤ 2 in both normal premature intestine and during NEC. In the absence of TGF-␤ signaling, SnoN/SKIL binds to the Smad7 promoter and maintains it in a state of repression (6,46). Our findings of decreased SnoN/SKIL expression in the premature intestine is consistent with existing information; SnoN/SKIL is expressed at very low levels in most cell types during the fetal period except for specific developmental epochs (25).…”

“…We considered several possible mechanism(s) to explain increased Smad7 expression in the preterm intestine and during NEC: 1) deficiency of SKI and/or SnoN/SKIL, corepressors of the Smad7 promoter (6,12,46); 2) deficiency of Fox-P3, which normally inhibits Smad7 expression (17); and 3) Smad7 induction by bacterial products and cytokines such as interferon-␥ (4, 49). FoxP3 was less relevant because it is not expressed in IECs (9), and similarly, LPS and interferon-␥ may be important during NEC but not in the normal premature intestine.…”

Arkadia Induces Degradation of SnoN and c-Ski to Enhance Transforming Growth Factor-β Signaling

“…Denissova and Liu (60) reported that c-Ski transcriptionally represses Smad7 expression. SnoN has also been reported to repress transcription of Smad7 by binding to the promoter region (61). Degradation of SnoN or c-Ski would reactivate transcription of Smad7 and then induce the expression of Smad7 protein.…”

Transforming Growth Factor-β/SMAD Target Gene SKIL Is Negatively Regulated by the Transcriptional Cofactor Complex SNON-SMAD4

“…So far, only a few TGF-␤ target genes have been shown to be directly regulated by SKI and SNON. The SMAD7 gene, a negative regulator of the TGF-␤ pathway, is likely the best characterized gene negatively regulated by SKI and SNON corepressors (12,13). In addition, SNON and SKI proteins can also be localized in the cytosol where they might be able to block TGF-␤ signals by sequestering SMAD proteins and preventing their translocation to the nucleus (5,14).…”

“…Interestingly, the TGF-␤/SMAD pathway regulates SNON protein levels in a biphasic manner: it causes a rapid and transient SNON protein degradation via the proteasome followed by an up-regulation of SNON mRNA and protein levels after a longer TGF-␤ treatment. This newly synthesized SNON protein seems to establish a negative feedback loop to turn off TGF-␤ signaling; this is an important but poorly understood event (13,23). The regulation of SNON expression is relevant because SNON has an essential role during embryonic development as well as in homeostasis in the adult organism.…”