This gene encodes a member of the Snail superfamily of C2H2-type zinc fingertranscription factors. The encoded protein acts as a transcriptional repressor that binds to E-box motifs and is also likely to repress E-cadherin transcription in breast carcinoma. This protein is involved in epithelial-mesenchymal transitions and has antiapoptotic activity. It regulates differentiation and migration of neural crest cells along with other genes (e.g. FOXD3, SOX9 and SOX10, BMPs) in embryonic life. Mutations in this gene may be associated with sporadic cases of neural tubedefects.[3]
Function
The human embryonic protein SNAI2, commonly known as SLUG, is a zinc finger transcriptional repressor which downregulates expression of E-cadherin in premigratory neural crest cells; thus, SNAI2 induces tightly bound epithelial cells to break into a loose mesenchymal phenotype, allowing gastrulation of mesoderm in the developing embryo.[4][5] Structurally similar to anti-apoptotic Ces-1 in C. elegans, SLUG is a negative regulator of productive cell death in the developing embryo and adults.[4][6]
Clinical significance
Widely expressed in human tissues, SLUG is most notably absent in peripheral blood leukocytes, adult liver, and both fetal and adult brain tissues.[6] SLUG plays a role in breast carcinoma as well as leukemia by downregulation of E-cadherin, which supports mesenchymal phenotype by shifting expression from a Type I to Type II cadherin profile.[6][7] Maintenance of mesenchymal phenotype enables metastasis of tumor cells, though SLUG is expressed in carcinomas regardless to invasiveness.[4][5][6] A knockout model using chick embryos has also showed inhibition of mesodermal and neural crest delamination; chick embryo Slug gain of function appears to increase neural crest production.[4] Mutations in Slug are associated with loss of pregnancy during gastrulation in some animals.[4]
Interactions
BMPs precede expression of SLUG, and are suspected as the immediate upstream inducers of gene expression.[5][8]
References
↑Rhim H, Savagner P, Thibaudeau G, Thiery JP, Pavan WJ (Jan 1998). "Localization of a neural crest transcription factor, Slug, to mouse chromosome 16 and human chromosome 8". Mammalian Genome. 8 (11): 872–3. doi:10.1007/s003359900601. PMID9337409.
↑Cohen ME, Yin M, Paznekas WA, Schertzer M, Wood S, Jabs EW (August 1998). "Human SLUG gene organization, expression, and chromosome map location on 8q". Genomics. 51 (3): 468–71. doi:10.1006/geno.1998.5367. PMID9721220.
↑ 4.04.14.24.34.4Nieto MA (March 2002). "The snail superfamily of zinc-finger transcription factors". Nature Reviews Molecular Cell Biology. 3 (3): 155–66. doi:10.1038/nrm757. PMID11994736.
↑ 5.05.15.2Carlson BM (2013). Human Embryology and Developmental Biology (5th ed.). Philadelphia, PA: Elsevier Health Sciences. pp. 101–102, 106, 313, 362, 382. ISBN978-1-4557-2794-0.
↑ 6.06.16.26.3Inukai T, Inoue A, Kurosawa H, Goi K, Shinjyo T, Ozawa K, Mao M, Inaba T, Look AT (September 1999). "SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein". Molecular Cell. 4 (3): 343–52. doi:10.1016/S1097-2765(00)80336-6. PMID10518215.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Stegmann K, Boecker J, Kosan C, Ermert A, Kunz J, Koch MC (August 1999). "Human transcription factor SLUG: mutation analysis in patients with neural tube defects and identification of a missense mutation (D119E) in the Slug subfamily-defining region". Mutation Research. 406 (2–4): 63–9. doi:10.1016/S1383-5726(99)00002-3. PMID10479723.
Inukai T, Inoue A, Kurosawa H, Goi K, Shinjyo T, Ozawa K, Mao M, Inaba T, Look AT (September 1999). "SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein". Molecular Cell. 4 (3): 343–52. doi:10.1016/S1097-2765(00)80336-6. PMID10518215.
Hajra KM, Chen DY, Fearon ER (March 2002). "The SLUG zinc-finger protein represses E-cadherin in breast cancer". Cancer Research. 62 (6): 1613–8. PMID11912130.
Sánchez-Martín M, Rodríguez-García A, Pérez-Losada J, Sagrera A, Read AP, Sánchez-García I (December 2002). "SLUG (SNAI2) deletions in patients with Waardenburg disease". Human Molecular Genetics. 11 (25): 3231–6. doi:10.1093/hmg/11.25.3231. PMID12444107.
Catalano A, Rodilossi S, Rippo MR, Caprari P, Procopio A (November 2004). "Induction of stem cell factor/c-Kit/slug signal transduction in multidrug-resistant malignant mesothelioma cells". The Journal of Biological Chemistry. 279 (45): 46706–14. doi:10.1074/jbc.M406696200. PMID15337769.
Uchikado Y, Natsugoe S, Okumura H, Setoyama T, Matsumoto M, Ishigami S, Aikou T (February 2005). "Slug Expression in the E-cadherin preserved tumors is related to prognosis in patients with esophageal squamous cell carcinoma". Clinical Cancer Research. 11 (3): 1174–80. PMID15709186.
Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, Notorfrancesco KL, Cardiff RD, Chodosh LA (September 2005). "The transcriptional repressor Snail promotes mammary tumor recurrence". Cancer Cell. 8 (3): 197–209. doi:10.1016/j.ccr.2005.07.009. PMID16169465.
Chen M, Chen LM, Chai KX (June 2006). "Androgen regulation of prostasin gene expression is mediated by sterol-regulatory element-binding proteins and SLUG". The Prostate. 66 (9): 911–20. doi:10.1002/pros.20325. PMID16541421.
Turner FE, Broad S, Khanim FL, Jeanes A, Talma S, Hughes S, Tselepis C, Hotchin NA (July 2006). "Slug regulates integrin expression and cell proliferation in human epidermal keratinocytes". The Journal of Biological Chemistry. 281 (30): 21321–31. doi:10.1074/jbc.M509731200. PMID16707493.