Zinc finger protein SNAI1 (sometime referred to as Snail) is a protein that in humans is encoded by the SNAI1gene.[1][2] Snail is a family of transcription factors that promote the repression of the adhesion molecule E-cadherin to regulate epithelial to mesenchymal transition (EMT) during embryonic development.
The Drosophila embryonic protein SNAI1, commonly known as Snail, is a zinc finger transcriptional repressor which downregulates the expression of ectodermal genes within the mesoderm. The nuclear protein encoded by this gene is structurally similar to the Drosophila snail protein, and is also thought to be critical for mesoderm formation in the developing embryo. At least two variants of a similar processed pseudogene have been found on chromosome 2.[2] SNAI1 zinc-fingers (ZF) binds to E-box, an E-cadherin promoter region,[3] and represses the expression of the adhesion molecule, which induces the tightly bound epithelial cells to break loose from each other and migrate into the developing embryo to become mesenchymal cells. This process allows for the formation of the mesodermal layer in the developing embryo. Though SNAI1 is shown to repress expression of E-cadherin in epithelial cells, studies have shown homozygous mutant embryos are still able to form a mesodermal layer.[4] However, the mesodermal layer present shows characteristics of epithelial cells and not mesenchymal cells (the mutant mesoderm cells exhibited a polarized state). Other studies show that mutation of specific ZFs contribute to a decrease in SNAI1 E-cadherin repression.[3]
SNAI1 and other epithelial-mesenchymal transition (EMT) genes are regulated by several genes and molecules including Wnt and prostaglandins. Wnt3a is a master regulator of paraxial presomatic mesoderm cells (PSM) which differentiate into the musculoskeleton of the trunk and tail. Other genes, most of which act downstream of Wnt include Msx1, Pax3, and Mesogenin 1 (Msgn1). Msgn1 activates SNAI1 by binding to its enhancer and activating SNAI1 to induce EMT. MSGN1 also regulates many of the same genes as SNAI1 to ensure EMT activation, granting the system redundancy. This suggests that Msgn1 and SNAI1 act together through a feed forward mechanism. When Msgn1 is deleted, the mesodermal progenitors do not move from the primitive streak (PS) but still show mesenchymal morphology. This suggests that the Msgn1/SNAI1 axis mostly functions to drive cell movement. [5] Prostaglandin E2 (PE2), an important hormone in homeostasis and maintaining normal fertility and pregnancy, stabilizes SNAI1 post-transcriptionally and, therefore, also plays a role in embryogenesis. When the prostaglandin signaling pathway is compromised, SNAI1 transcriptional repressor activity decreases, increasing E-cadherin protein levels during gastrulation. However, this does not prevent gastrulation from occurring. [6]
Clinical significance
Snail gene may show a role in recurrence of breast cancer by downregulating E-cadherin and inducing an epithelial to mesenchymal transition.[7] The process of EMT is also noted as an important and noteworthy process in tumor growth, through the invasion and metastasis of tumor cells due to repression of E-cadherin adhesion molecules. Through knockout models, one study has shown the importance of SNAI1 in the growth of breast cancer cells.[8] Knockout models showed significant reduction in cancer invasiveness and therefore can be used as a therapeutic measure for the treatment of breast cancer before chemotherapy treatment.[8]
↑Paznekas WA, Okajima K, Schertzer M, Wood S, Jabs EW (November 1999). "Genomic organization, expression, and chromosome location of the human SNAIL gene (SNAI1) and a related processed pseudogene (SNAI1P)". Genomics. 62 (1): 42–9. doi:10.1006/geno.1999.6010. PMID10585766.
↑Carver EA, Jiang R, Lan Y, Oram KF, Gridley T (December 2001). "The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition". Molecular and Cellular Biology. 21 (23): 8184–8. doi:10.1128/MCB.21.23.8181-8188.2001. PMID11689706.
↑Chalamalasetty RB, Garriock RJ, Dunty WC, Kennedy MW, Jailwala P, Si H, Yamaguchi TP (November 2014). "Mesogenin 1 is a master regulator of paraxial presomitic mesoderm differentiation". Development. 141 (22): 4285–97. doi:10.1242/dev.110908. PMID25371364.
↑Speirs CK, Jernigan KK, Kim SH, Cha YI, Lin F, Sepich DS, DuBois RN, Lee E, Solnica-Krezel L (April 2010). "Prostaglandin Gbetagamma signaling stimulates gastrulation movements by limiting cell adhesion through Snai1a stabilization". Development. 137 (8): 1327–37. doi:10.1242/dev.045971. PMID20332150.
↑ 8.08.1Olmeda D, Moreno-Bueno G, Flores JM, Fabra A, Portillo F, Cano A (December 2007). "SNAI1 is required for tumor growth and lymph node metastasis of human breast carcinoma MDA-MB-231 cells". Cancer Research. 67 (24): 11721–31. doi:10.1158/0008-5472.can-07-2318. PMID18089802.
Twigg SR, Wilkie AO (October 1999). "Characterisation of the human snail (SNAI1) gene and exclusion as a major disease gene in craniosynostosis". Human Genetics. 105 (4): 320–6. doi:10.1007/s004390051108. PMID10543399.
Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J, García De Herreros A (February 2000). "The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells". Nature Cell Biology. 2 (2): 84–9. doi:10.1038/35000034. PMID10655587.
Smith S, Metcalfe JA, Elgar G (April 2000). "Identification and analysis of two snail genes in the pufferfish (Fugu rubripes) and mapping of human SNA to 20q". Gene. 247 (1–2): 119–28. doi:10.1016/S0378-1119(00)00110-4. PMID10773451.
Okubo T, Truong TK, Yu B, Itoh T, Zhao J, Grube B, Zhou D, Chen S (February 2001). "Down-regulation of promoter 1.3 activity of the human aromatase gene in breast tissue by zinc-finger protein, snail (SnaH)". Cancer Research. 61 (4): 1338–46. PMID11245431.
Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J, Nieto MA (May 2002). "Correlation of Snail expression with histological grade and lymph node status in breast carcinomas". Oncogene. 21 (20): 3241–6. doi:10.1038/sj.onc.1205416. PMID12082640.
Guaita S, Puig I, Franci C, Garrido M, Dominguez D, Batlle E, Sancho E, Dedhar S, De Herreros AG, Baulida J (October 2002). "Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression". The Journal of Biological Chemistry. 277 (42): 39209–16. doi:10.1074/jbc.M206400200. PMID12161443.
Yokoyama K, Kamata N, Fujimoto R, Tsutsumi S, Tomonari M, Taki M, Hosokawa H, Nagayama M (April 2003). "Increased invasion and matrix metalloproteinase-2 expression by Snail-induced mesenchymal transition in squamous cell carcinomas". International Journal of Oncology. 22 (4): 891–8. doi:10.3892/ijo.22.4.891. PMID12632084.
Ikenouchi J, Matsuda M, Furuse M, Tsukita S (May 2003). "Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail". Journal of Cell Science. 116 (Pt 10): 1959–67. doi:10.1242/jcs.00389. PMID12668723.
Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC (October 2004). "Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition". Nature Cell Biology. 6 (10): 931–40. doi:10.1038/ncb1173. PMID15448698.
Saito T, Oda Y, Kawaguchi K, Sugimachi K, Yamamoto H, Tateishi N, Tanaka K, Matsuda S, Iwamoto Y, Ladanyi M, Tsuneyoshi M (November 2004). "E-cadherin mutation and Snail overexpression as alternative mechanisms of E-cadherin inactivation in synovial sarcoma". Oncogene. 23 (53): 8629–38. doi:10.1038/sj.onc.1207960. PMID15467754.