SNAI1

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External IDs	GeneCards: [1]
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Species	Human	Mouse
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Zinc finger protein SNAI1 (sometimes referred to as Snail) is a protein that in humans is encoded by the SNAI1 gene. 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.

Function

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. SNAI1 zinc-fingers (ZF) binds to E-box, an E-cadherin promoter region, 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. 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.

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. 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.

Clinical significance

Snail gene may show a role in recurrence of breast cancer by downregulating E-cadherin and inducing an epithelial to mesenchymal transition. 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. 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.

Interactions

SNAI1 has been shown to interact with CTDSPL, CTDSP1 and CTDSP2.

Further reading

• 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. PMID 10543399.
• 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. PMID 10655587.
• 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. PMID 10773451.
• 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. PMID 11245431.
• 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. PMID 12082640.
• 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. PMID 12161443.
• 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. PMID 12632084.
• 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. PMID 12668723.
• Domínguez D, Montserrat-Sentís B, Virgós-Soler A, Guaita S, Grueso J, Porta M, Puig I, Baulida J, Francí C, García de Herreros A (July 2003). "Phosphorylation regulates the subcellular location and activity of the snail transcriptional repressor". Molecular and Cellular Biology. 23 (14): 5078–89. doi:10.1128/MCB.23.14.5078-5089.2003. PMC 162233. PMID 12832491.
• Imai T, Horiuchi A, Wang C, Oka K, Ohira S, Nikaido T, Konishi I (October 2003). "Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells". The American Journal of Pathology. 163 (4): 1437–47. doi:10.1016/S0002-9440(10)63501-8. PMC 1868286. PMID 14507651.
• Miyoshi A, Kitajima Y, Sumi K, Sato K, Hagiwara A, Koga Y, Miyazaki K (March 2004). "Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells". British Journal of Cancer. 90 (6): 1265–73. doi:10.1038/sj.bjc.6601685. PMC 2409652. PMID 15026811.
• Ohkubo T, Ozawa M (April 2004). "The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulation". Journal of Cell Science. 117 (Pt 9): 1675–85. doi:10.1242/jcs.01004. PMID 15075229.
• Barberà MJ, Puig I, Domínguez D, Julien-Grille S, Guaita-Esteruelas S, Peiró S, Baulida J, Francí C, Dedhar S, Larue L, García de Herreros A (September 2004). "Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells". Oncogene. 23 (44): 7345–54. doi:10.1038/sj.onc.1207990. PMID 15286702.
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (August 2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proceedings of the National Academy of Sciences of the United States of America. 101 (33): 12130–5. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
• Kajita M, McClinic KN, Wade PA (September 2004). "Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress". Molecular and Cellular Biology. 24 (17): 7559–66. doi:10.1128/MCB.24.17.7559-7566.2004. PMC 506998. PMID 15314165.
• 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. PMID 15448698.
• 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. PMID 15467754.