Biology:ZEB2

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

Zinc finger E-box-binding homeobox 2 is a protein that in humans is encoded by the ZEB2 gene. The ZEB2 protein is a transcription factor that plays a role in the transforming growth factor β (TGFβ) signaling pathways that are essential during early fetal development.

Function

ZEB2 (previously also known as SMADIP1, SIP1) and its mammalian paralog ZEB1 belongs to the Zeb family within the ZF (zinc finger) class of homeodomain transcription factors. ZEB2 protein has 8 zinc fingers and 1 homeodomain. The structure of the homeodomain shown on the right.

ZEB2 interacts with receptor-mediated, activated full-length SMADs. The activation of TGFβ receptors brings about the phosphorylation of intracellular effector molecules, R-SMADs. ZEB2 is an R-SMAD-binding protein and acts as a transcriptional corepressor. It is involved in the timing of the conversion of neuroepithelial cells into radial glial cells in early development, a mechanism thought to allow for the large differences in brain size between humans and other mammals.

ZEB2 transcripts are found in tissues differentiated from the neural crest such as the cranial nerve ganglia, dorsal root ganglia, sympathetic ganglionic chains, the enteric nervous system and melanocytes. ZEB2 is also found in tissues that are not derived from the neural crest, including the wall of the digestive tract, kidneys, and skeletal muscles.

Clinical significance

Mutations in the ZEB2 gene are associated with the Mowat–Wilson syndrome. This disease exhibits mutations and even complete deletions of the ZEB2 gene. Mutations of the gene can cause the gene to produce nonfunctional ZEB2 proteins or inactivate the function gene as a whole. These deficits of ZEB2 protein interfere with the development of many organs. Many of the symptoms can be explained by the irregular development of the structures from the neural crest.

Hirschsprung's disease also has many symptoms that can be explained by lack of ZEB2 during development of the digestive tract nerves. This disease causes severe constipation and enlargement of the colon.

Further reading

• "Mowat-Wilson syndrome". Journal of Medical Genetics 40 (5): 305–10. May 2003. doi:10.1136/jmg.40.5.305. PMID 12746390. 
• "Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Research 5 (1): 31–9. February 1998. doi:10.1093/dnares/5.1.31. PMID 9628581. 
• "Selection system for genes encoding nuclear-targeted proteins". Nature Biotechnology 16 (13): 1338–42. December 1998. doi:10.1038/4315. PMID 9853615. 
• "SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5'-CACCT sequences in candidate target genes". The Journal of Biological Chemistry 274 (29): 20489–98. July 1999. doi:10.1074/jbc.274.29.20489. PMID 10400677. 
• "Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease". Nature Genetics 27 (4): 369–70. April 2001. doi:10.1038/86860. PMID 11279515. 
• "The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion". Molecular Cell 7 (6): 1267–78. June 2001. doi:10.1016/S1097-2765(01)00260-X. PMID 11430829. 
• "Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease". Human Molecular Genetics 10 (14): 1503–10. July 2001. doi:10.1093/hmg/10.14.1503. PMID 11448942. 
• "Smad-interacting protein 1 is a repressor of liver/bone/kidney alkaline phosphatase transcription in bone morphogenetic protein-induced osteogenic differentiation of C2C12 cells". The Journal of Biological Chemistry 276 (43): 40001–7. October 2001. doi:10.1074/jbc.M104112200. PMID 11477103. 
• "Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features". American Journal of Human Genetics 69 (6): 1178–85. December 2001. doi:10.1086/324343. PMID 11592033. 
• "Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures". American Journal of Human Genetics 69 (6): 1370–7. December 2001. doi:10.1086/324342. PMID 11595972. 
• ""Mowat-Wilson" syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene". American Journal of Medical Genetics 108 (3): 177–81. March 2002. doi:10.1002/ajmg.10226. PMID 11891681. 
• "Clinical features of a form of Hirschsprung's disease caused by a novel genetic abnormality". Journal of Pediatric Surgery 37 (8): 1117–22. August 2002. doi:10.1053/jpsu.2002.34455. PMID 12149685. 
• "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. October 2002. doi:10.1074/jbc.M206400200. PMID 12161443. 
• "Expression of the SMADIP1 gene during early human development". Mechanisms of Development 114 (1–2): 187–91. June 2002. doi:10.1016/S0925-4773(02)00062-X. PMID 12175509. 
• "Late infantile Hirschsprung disease-mental retardation syndrome with a 3-bp deletion in ZFHX1B". Neurology 59 (10): 1637–40. November 2002. doi:10.1212/01.wnl.0000034842.78350.4e. PMID 12451214. 
• "Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway". The EMBO Journal 22 (10): 2443–52. May 2003. doi:10.1093/emboj/cdg225. PMID 12743038. 
• "Regulation of Smad signaling through a differential recruitment of coactivators and corepressors by ZEB proteins". The EMBO Journal 22 (10): 2453–62. May 2003. doi:10.1093/emboj/cdg226. PMID 12743039. 
• "Characterisation of deletions of the ZFHX1B region and genotype-phenotype analysis in Mowat-Wilson syndrome". Journal of Medical Genetics 40 (8): 601–5. August 2003. doi:10.1136/jmg.40.8.601. PMID 12920073. 

External links

• GeneReviews/NIH/NCBI/UW entry on Mowat-Wilson syndrome
• ZEB2+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)