Alternative titles; symbols
HGNC Approved Gene Symbol: SFN
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38): 1:26,863,149-26,864,456 (from NCBI)
SFN, or 14-3-3-sigma, is a regulator of mitotic translation that interacts with a variety of translation and initiation factors (Wilker et al., 2007).
Leffers et al. (1993) obtained peptide sequence and subsequently cloned a T-cell cDNA of the 14-3-3 family (see 113508) of conserved proteins. The protein, called stratifin, was shown to be diffusely distributed in the cytoplasm and was present in cultured epithelial cells. It was most abundant in tissues enriched in stratified keratinizing epithelium.
Hermeking et al. (1997) mapped the SFN gene to chromosome 1p35 using fluorescence in situ hybridization.
Through a quantitative analysis of gene expression patterns in colorectal cancer cell lines, Hermeking et al. (1997) discovered that 14-3-3-sigma, or stratifin, is strongly induced by gamma irradiation and other DNA-damaging agents. The induction of 14-3-3-sigma is mediated by a p53 (191170)-responsive element located 1.8 kb upstream of its transcription start site. Exogenous introduction of 14-3-3-sigma into cycling cells results in a G2 arrest. As the fission yeast 14-3-3 homologs rad24 and rad25 mediate similar checkpoint effects, Hermeking et al. (1997) concluded that the results document a molecular mechanism for G2/M control that is conserved throughout eukaryotic evolution and regulated in human cells by p53.
Chan et al. (1999) described an improved approach to the generation of human somatic cell knockouts, which they used to generate human colorectal cancer cells in which both 14-3-3-sigma alleles were inactivated. After DNA damage, these cells initially arrested in the G2 phase of the cell cycle, but unlike cells containing 14-3-3-sigma, the 14-3-3-sigma -/- cells were unable to maintain cell cycle arrest. The 14-3-3-sigma -/- cells died (mitotic catastrophe) as they entered mitosis. This process was associated with a failure of the 14-3-3-sigma-deficient cells to sequester the proteins (cyclin B, 123836; CDC2, 116940) that initiate mitosis and prevent them from entering the nucleus. Chan et al. (1999) concluded that these results indicated a mechanism for maintaining the G2 checkpoint and preventing mitotic death.
Expression of 14-3-3-sigma is induced in response to DNA damage, and causes cells to arrest in G2. By SAGE, Ferguson et al. (2000) identified sigma as a gene whose expression is 7-fold lower in breast carcinoma cells than in normal breast epithelium. Although genetic alterations at the SFN locus such as loss of heterozygosity were rare and no mutations were detected, the authors found that hypermethylation of CpG islands in the SFN gene could be detected in 91% of breast tumors and was associated with lack of gene expression. Treatment of sigma-nonexpressing breast cancer cell lines with the drug 5-aza-2-prime-deoxycytidine resulted in demethylation of the gene and synthesis of sigma mRNA. Breast cancer cells lacking sigma expression showed an increased number of chromosomal breaks and gaps when exposed to gamma-irradiation. Ferguson et al. (2000) thought it possible that loss of sigma expression contributes to malignant transformation by impairing the G2 cell cycle checkpoint function, thus allowing an accumulation of genetic defects. They suggested that hypermethylation and loss of sigma expression were the most consistent molecular alterations identified in breast cancer.
Urano et al. (2002) demonstrated that EFP (600453) is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3-sigma, a negative cell cycle regulator that causes G2 arrest. Urano et al. (2002) demonstrated that tumor growth of breast cancer MCF7 cells implanted in female athymic mice is reduced by treatment with antisense Efp oligonucleotide. Efp-overexpressing MCF7 cells in ovariectomized athymic mice generated tumors in the absence of estrogen. Loss of Efp function in mouse embryonic fibroblasts resulted in an accumulation of 14-3-3-sigma, which was responsible for reduced cell growth. Urano et al. (2002) concluded that their data provide an insight into the cell cycle machinery and tumorigenesis of breast cancer by identifying 14-3-3-sigma as a target for proteolysis by EFP, leading to cell proliferation.
Wilker et al. (2007) reported a previously unknown function for 14-3-3-sigma as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B (EIF4B; 603928) in a stoichiometric manner. Cells lacking 14-3-3-sigma, in marked contrast to normal cells, cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase CDK11 (p58 PITSLRE; 176873), leading to impaired cytokinesis, loss of Polo-like kinase-1 (602098) at the midbody, and the accumulation of binucleate cells. The aberrant mitotic phenotype of 14-3-3-sigma-depleted cells can be rescued by forced expression of CDK11 or by extinguishing cap-dependent translation and increasing cap-independent translation during mitosis by using rapamycin. Wilker et al. (2007) concluded that their findings showed how aberrant mitotic translation in the absence of 14-3-3-sigma impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3-sigma-deficient cells may progress on the path to aneuploidy and tumorigenesis.
A large proportion of aggressive squamous cell carcinomas in humans and mice express markedly reduced IKKA (CHUK; 600664), and somatic mutations in IKKA have been identified in human squamous cell carcinomas. Zhu et al. (2007) identified 14-3-3-sigma as a downstream target of Ikka in cell cycle regulation in response to DNA damage and found that the 14-3-3-sigma locus was hypermethylated in Ikka -/- mouse keratinocytes, but not in wildtype keratinocytes. Trimethylated histone H3-lys9 (see 602810) associated with Suv39h1 (300254) and Dnmt3a (602769) in the methylated 14-3-3-sigma locus. Reintroduction of Ikka restored 14-3-3-sigma expression by associating with H3 and preventing access of Suv39h1 to H3, thereby preventing hypermethylation of 14-3-3-sigma. Zhu et al. (2007) concluded that IKKA protects the 14-3-3-sigma locus from hypermethylation, which serves as a mechanism of maintaining genomic stability in keratinocytes.
Choi et al. (2011) showed that the ubiquitin ligase COP1 (RFWD2; 608067) targeted 14-3-3-sigma for ubiquitin-mediated degradation in human cell lines. The COP9 signalosome subunit COPS6 (614729) stabilized COP1 by reducing COP1 autoubiquitination, resulting in elevated 14-3-3-sigma ubiquitination and degradation.
The 14-3-3 family of proteins mediates signal transduction by binding to phosphoserine-containing proteins. Using phosphoserine-oriented peptide libraries to probe all mammalian and yeast 14-3-3s, Yaffe et al. (1997) identified 2 different binding motifs, RSXpSXP and RXY/FXpSXP, present in nearly all known 14-3-3 binding proteins. The crystal structure of YWHAZ (601288) complexed with the phosphoserine motif in polyoma middle-T was determined to 2.6-angstrom resolution. The authors showed that the 14-3-3 dimer binds tightly to single molecules containing tandem repeats of phosphoserine motifs, implicating bidentate association as a signaling mechanism with molecules such as Raf, BAD (603167), and Cbl.
Stratifin is highly expressed in differentiating epidermis and mediates cell cycle arrest. To extend understanding of skin development, Herron et al. (2005) set out to identify the causal mutation in 'repeated epilation' (Er) mutant mice. The heterozygous mutant (Er/+) mouse was originally identified in the offspring of a male exposed to gamma radiation; the mutant had a disheveled appearance at 3 weeks of age. Older heterozygous mice had an increased incidence of papillomas and squamous cell carcinomas. Linkage studies localized the Er gene to mouse chromosome 4 in an 820-kb region containing 22 genes. Among these genes, Sfn was considered a good candidate for underlying the Er mutation because it has a role in keratinocyte differentiation and because Sfn expression is abnormal in epithelial cancers. Sequencing of the Sfn open reading frame in genomic DNA from homozygous Er/Er and wildtype mice detected a single T insertion at basepair 622 in homozygous mutant mice. This frameshift mutation at amino acid 207 truncates the C terminus of the protein encoded by the Er allele, eliminating residues required for ligand interaction and the nuclear export sequence.
By gene expression analysis of skin and embryonic fibroblasts from wildtype and Er mice, Li et al. (2005) identified a 1-bp insertion (642insT) in the Sfn gene that results in the Er phenotype. The insertion causes a frameshift leading to a truncated protein lacking 40 amino acids at the C terminus. Li et al. (2005) noted that Er/+ adult mice showed repeated hair loss, whereas Er/Er mutant mice died at birth due to respiratory distress and skin defects, with hyperplastic epidermis, failure of keratinocyte differentiation, and abnormal craniofacial development. Ectopic overexpression of Sfn in Er/Er keratinocytes rescued the defects of keratinocyte differentiation.
Chan, T. A., Hermeking, H., Langauer, C., Kinzler, K. W., Vogelstein, B. 14-3-3-sigma is required to prevent mitotic catastrophe after DNA damage. Nature 401: 616-620, 1999. Note: Erratum: Nature: 621: E28-E29, 2023. [PubMed: 10524633] [Full Text: https://doi.org/10.1038/44188]
Choi, H. H., Gully, C., Su, C.-H., Velazquez-Torres, G., Chou, P.-C., Tseng, C., Zhao, R., Phan, L., Shaiken, T., Chen, J., Yeung, S. C., Lee, M.-H. COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3-sigma. Oncogene 30: 4791-4801, 2011. [PubMed: 21625211] [Full Text: https://doi.org/10.1038/onc.2011.192]
Ferguson, A. T., Evron, E., Umbricht, C. B., Pandita, T. K., Chan, T. A., Hermeking, H., Marks, J. R., Lambers, A. R., Futreal, P. A., Stampfer, M. R., Sukumar, S. High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer. Proc. Nat. Acad. Sci. 97: 6049-6054, 2000. [PubMed: 10811911] [Full Text: https://doi.org/10.1073/pnas.100566997]
Hermeking, H., Lengauer, C., Polyak, K., He, T.-C., Zhang, L., Thiagalingam, S., Kinzler, K. W., Vogelstein, B. 14-3-3-sigma is a p53-regulated inhibitor of G2/M progression. Molec. Cell 1: 3-11, 1997. [PubMed: 9659898] [Full Text: https://doi.org/10.1016/s1097-2765(00)80002-7]
Herron, B. J., Liddell, R. A., Parker, A., Grant, S., Kinne, J., Fisher, J. K., Siracusa, L. D. A mutation in stratifin is responsible for the repeated epilation (Er) phenotype in mice. Nature Genet. 37: 1210-1212, 2005. [PubMed: 16200063] [Full Text: https://doi.org/10.1038/ng1652]
Leffers, H., Madsen, P., Rasmussen, H. H., Honore, B., Andersen, A. H., Walbum, E., Vandekerckhove, J., Celis, J. E. Molecular cloning and expression of the transformation sensitive epithelial marker stratifin: a member of a protein family that has been involved in the protein kinase C signalling pathway. J. Molec. Biol. 231: 982-998, 1993. [PubMed: 8515476] [Full Text: https://doi.org/10.1006/jmbi.1993.1346]
Li, Q., Lu, Q., Estepa, G., Verma, I. M. Identification of 14-3-3-sigma mutation causing cutaneous abnormality in repeated-epilation mutant mouse. Proc. Nat. Acad. Sci. 102: 15977-15982, 2005. [PubMed: 16239341] [Full Text: https://doi.org/10.1073/pnas.0508310102]
Urano, T., Saito, T., Tsukui, T., Fujita, M., Hosoi, T., Muramatsu, M., Ouchi, Y., Inoue, S. Efp targets 14-3-3-sigma for proteolysis and promotes breast tumour growth. Nature 417: 871-875, 2002. [PubMed: 12075357] [Full Text: https://doi.org/10.1038/nature00826]
Wilker, E. W., van Vugt, M. A. T. M., Artim, S. A., Huang, P. H., Petersen, C. P., Reinhardt, H. C., Feng, Y., Sharp, P. A., Sonenberg, N., White, F. M., Yaffe, M. B. 14-3-3-sigma controls mitotic translation to facilitate cytokinesis. Nature 446: 329-332, 2007. [PubMed: 17361185] [Full Text: https://doi.org/10.1038/nature05584]
Yaffe, M. B., Rittinger, K., Volinia, S., Caron, P. R., Aitken, A., Leffers, H., Gamblin, S. J., Smerdon, S. J., Cantley, L. C. The structural basis for 14-3-3:phosphopeptide binding specificity. Cell 91: 961-971, 1997. [PubMed: 9428519] [Full Text: https://doi.org/10.1016/s0092-8674(00)80487-0]
Zhu, F., Xia, X., Liu, B., Shen, J., Hu, Y., Person, M., Hu, Y. IKK-alpha shields 14-3-3-sigma, a G2/M cell cycle checkpoint gene, from hypermethylation, preventing its silencing. Molec. Cell 27: 214-227, 2007. [PubMed: 17643371] [Full Text: https://doi.org/10.1016/j.molcel.2007.05.042]