Alternative titles; symbols
HGNC Approved Gene Symbol: SKIL
Cytogenetic location: 3q26.2 Genomic coordinates (GRCh38): 3:170,357,715-170,396,849 (from NCBI)
Nomura et al. (1989) isolated human cDNA clones of SKI (164780) and a SKI-related gene, SNO (SKI-related novel gene). Two distinct cDNA clones were isolated for the SNO gene; the first, SNO-N (non-Alu-containing), encodes a 684-amino acid protein, while the second, SNO-A (Alu-containing), encodes a 415-amino acid protein.
The mouse Sno gene expresses 2 isoforms, SnoN and SnoN2, that are different from each other in a location downstream of the site of alternative splicing previously described in the human SNO gene. SnoN2 is missing a 138-bp coding segment present in mouse SnoN and human SNON. Pearson-White and Crittenden (1997) cloned and sequenced the human ortholog of mouse SnoN2, the existence of which was predicted from conservation of the alternative splice donor site that produces the SnoN2 isoform. In the mouse the 2 isoforms are expressed throughout embryonic development in neonatal muscle and in many adult tissues. SnoN2 is the major species in most tissues, but SnoN and SnoN2 are expressed at approximately equal levels in brain. In human tissues, SNON2 is the less abundantly expressed isoform. Expression of mRNAs of both isoforms is induced with immediate early kinetics upon serum stimulation of quiescent fibroblasts, even in the presence of the protein synthesis inhibitor cycloheximide. Pearson-White and Crittenden (1997) concluded that the data are consistent with a role of SNO in the response to proliferation stimuli.
Gross (2014) mapped the SKIL gene to chromosome 3q26.2 based on an alignment of the SKIL sequence (GenBank BC059386) with the genomic sequence (GRCh37).
SMAD proteins mediate transforming growth factor-beta (TGFB; 190180) signaling to regulate cell growth and differentiation. Stroschein et al. (1999) identified SnoN as a component of the SMAD pathway. They proposed a model of regulation of TGFB signaling by SnoN in which SnoN maintains the repressed state of TGFB target genes in the absence of ligand and participates in the negative feedback regulation of TGFB signaling. In the absence of TGFB, SnoN binds to the nuclear SMAD4 (600993) and represses TGFB-responsive promoter activity through recruitment of a nuclear repressor complex. TGFB induces activation and nuclear translocation of SMAD2 (601366), SMAD3 (603109), and SMAD4. SMAD3 causes degradation of SnoN, allowing a SMAD2/SMAD4 complex to activate TGFB target genes. To initiate a negative feedback mechanism that permits a precise and timely regulation of TGFB signaling, TGFB also induces an increased expression of SnoN at a later stage, which in turn binds to SMAD heteromeric complexes and shuts off TGFB signaling.
Degradation of SnoN is thought to play an important role in the transactivation of TGFB-responsive genes. Wan et al. (2001) demonstrated that the anaphase-promoting complex (APC) is a ubiquitin ligase required for the destruction of SnoN and that the APC pathway is regulated by TGFB. The destruction box of SnoN is required for its degradation in response to TGFB signaling. Furthermore, the APC activator CDH1 (192090) and SMAD3 synergistically regulate SnoN degradation. Under these circumstances, CDH1 forms a quaternary complex with SnoN, SMAD3, and APC.
Gross, M. B. Personal Communication. Baltimore, Md. 5/27/2014.
Nomura, N., Sasamoto, S., Ishii, S., Date, T., Matsui, M., Ishizaki, R. Isolation of human cDNA clones of SKI and the SKI-related gene, SNO. Nucleic Acids Res. 17: 5489-5500, 1989. [PubMed: 2762147] [Full Text: https://doi.org/10.1093/nar/17.14.5489]
Pearson-White, S., Crittenden, R. Proto-oncogene Sno expression, alternative isoforms and immediate early serum response. Nucleic Acids Res. 25: 2930-2937, 1997. [PubMed: 9207045] [Full Text: https://doi.org/10.1093/nar/25.14.2930]
Stroschein, S. L., Wang, W., Zhou, S., Zhou, Q., Luo, K. Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science 286: 771-774, 1999. [PubMed: 10531062] [Full Text: https://doi.org/10.1126/science.286.5440.771]
Wan, Y., Liu, X., Kirschner, M. W. The anaphase-promoting complex mediates TGF-beta signaling by targeting SnoN for destruction. Molec. Cell 8: 1027-1039, 2001. [PubMed: 11741538] [Full Text: https://doi.org/10.1016/s1097-2765(01)00382-3]