Biology:DACH1

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Dachshund homolog 1, also known as DACH1, is a protein which in humans is encoded by the DACH1 gene.[1][2][3] DACH1 has been shown to interact with Ubc9,[4] Smad4,[5] and NCoR.[5][6]

Structure

Gene structure . This protein coding gene has 760 amino acid protein, and an observed molecular weight of 52 kDa. Dachshund Family transcription factor 1 is encoded by DACH gene, who spans 400kDa and is encoded by 12 exons. This gene is located, in humans, in chromosome 13 (13q22). It encodes a chromatin-associated protein that associates with other DNA-binding transcription factors to regulate gene expression,[5][7][8][6][9][10] mRNA translation,[11] coactivator binding,[12] and cell fate determination during development.[13][14]

Multiple transcript variants encoding different isoforms have been found for this gene. Four alternatively spliced transcripts encoding different isoforms have been described for this gene.DACH1 mRNA was detected in multiple human tissues, including kidney and heart. Dach1 is located in nuclear and cytoplasmic pools and is considered a cell fate determination factor.[13][14] Dachshund domain 1 (DD1, also known as Box-N) has a predicted helix–turn–helix family structure. The X-ray crystal structure of the human DACH1 Box-N illustrates that the DACH1 protein contains a domain that is conserved with the pro-oncogenes ski/sno oncogenes, which form an α/β structure similar to that found in the winged helix/forkhead subgroup of DNA binding proteins.[10] This protein is widely expressed including bone marrow, brain, colon, eye, heart, kidney, leucocyte, liver, lung, pancreas, pineal gland, placenta, prostate, retina, skeletal muscle, small intestine, stromal/preosteoblasts and the spleen.[6][15][16]

Protein modification. DACH1 is modified by phosphorylation,[11] acetylation,[17] and SUMOYlation.[18] Acetylation of Dach1 determine binding to the p53 tumor suppressor, and thereby governs a subset of p53 functions involved in stem cell restraint and the inhibition of cellular proliferation.[17] SUMOYlation of DACH governs HDAC binding.[19] Phosphorylation of Dach1 contributes to YB-1 binding, subcellular distribution and the induction of EMT via translation of EMT regulatory genes.[11]

DACH1 Secondary Structure.[20]

Function

Organismal development. Dach1 is similar to the D. melanogaster dac gene, which encodes a nuclear factor essential for determining cell fates in the eye, leg, and nervous system of the fly.[2] Dach is a member of the Ski gene family and is involved in eye and organismal development.[14][21] Dach1 deletion mice exhibit early postnatal death, although no developmental defects were detected in any organ system examined, including kidneys. DACH1 plays an important role on this precursor of cell proliferation in retinal and pituitary.[3][13][22]

Restrain of Cancer cell growth. DACH1 protein is able to prevent the proliferation of cancerous cells (lung, breast, prostate[7][8][6][9][10]) and functions as a repressor of estrogen receptor activity in breast cancer cells.[7][9]

Transcription. DACH1 conducts transcriptional function through interacting with transcription factors including c-Jun,[7] estrogen receptor alpha,[9] the androgen receptor,[6] and the basal transcription apparatus through binding to the co-integrator protein CA150. Curiously, DACH1 selectively bound to the delta domain of c-Jun, which was known to interact with an endogenous cellular repressor. DACH1 binds directly with a Forkhead-like DNA sequence to restrain oncogenic signals from a subset of FKHR proteins.[10] Dach1 governs mRNA translation of an EMT signature[11] and governs Snail1 transcription.[11]

Cell migration. DACH1 inhibits migration of vascular endothelial cells,[19][23] fibroblasts[24] and prostate epithelial cells[23] wherein DACH1 maintains persistence of migratory directionality via heterotypic signals.

Disease relevance

Cancer

DACH1 has been implicated in suppression of tumor growth, and has been proposed as a putatative tumor suppressor although no formal in vivo evidence has been published to date. Supporting evidence includes the finding that Dach1 expression is reduced in human malignancies including breast,[22][11] lung,[8] prostate[6] and brain tumors.[25] DACH1 inhibits Cyclin D1 expression and thereby reduces breast cancer cell line cell growth.[24] Normal cells and some breast cancer cells have receptors that bind estrogen and progesterone. These two hormones often promote the growth of breast cancer cells. Approximately 70% of breast cancers are ERa+, DACH1 expression decreases when the cancer is more invasive and the level of estrogen is high.[9]

Nephropathy

Renal hypodysplasia (RHD) is characterized by small and/or disorganized kidneys following abnormal organogenesis. Double homozygous missense mutations of DACH1 and BMP4 occurred in a patient with bilateral cystic dysplasia.[26] Functional analysis of the DACH1 mutation (p.R684C). demonstrated enhanced suppression of the TGF-β pathway. Dach1 is highly expressed in the adult podocyte, with transcripts showing an approximate tenfold enrichment compared to total kidney cortex. It is also more widely expressed in the earlier developing kidney, but again including definite podocyte expression.

Diabetes

Hepatocyte the abundance of DACH1 Is Increased in the hepatocytes of Obese patients. Dach1 promotes hepatic insulin resistance via Nuclear Exclusion of HDAC4.[19]

References

  1. ↑ "Gene: DACH1 (ENSG00000276644) - Summary - Homo sapiens - Ensembl genome browser 89" (in en-gb). http://may2017.archive.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000276644;r=13:71437966-71867192. 
  2. ↑ 2.0 2.1 "dachshund encodes a nuclear protein required for normal eye and leg development in Drosophila". Development 120 (12): 3473–86. December 1994. doi:10.1242/dev.120.12.3473. PMID 7821215. 
  3. ↑ 3.0 3.1 "Ectopic eye development in Drosophila induced by directed dachshund expression". Development 124 (1): 45–52. January 1997. doi:10.1242/dev.124.1.45. PMID 9006066. 
  4. ↑ "Yeast two-hybrid system identifies the ubiquitin-conjugating enzyme mUbc9 as a potential partner of mouse Dac". Mechanisms of Development 97 (1–2): 3–12. October 2000. doi:10.1016/s0925-4773(00)00402-0. PMID 11025202. 
  5. ↑ 5.0 5.1 5.2 "DACH1 inhibits transforming growth factor-beta signaling through binding Smad4". The Journal of Biological Chemistry 278 (51): 51673–84. December 2003. doi:10.1074/jbc.M310021200. PMID 14525983. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "The cell fate determination factor dachshund inhibits androgen receptor signaling and prostate cancer cellular growth". Cancer Research 69 (8): 3347–55. April 2009. doi:10.1158/0008-5472.CAN-08-3821. PMID 19351840. 
  7. ↑ 7.0 7.1 7.2 7.3 "Cell fate determination factor DACH1 inhibits c-Jun-induced contact-independent growth". Molecular Biology of the Cell 18 (3): 755–67. March 2007. doi:10.1091/mbc.E06-09-0793. PMID 17182846. 
  8. ↑ 8.0 8.1 8.2 "Dachshund binds p53 to block the growth of lung adenocarcinoma cells". Cancer Research 73 (11): 3262–74. June 2013. doi:10.1158/0008-5472.CAN-12-3191. PMID 23492369. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 "The cell fate determination factor DACH1 is expressed in estrogen receptor-alpha-positive breast cancer and represses estrogen receptor-alpha signaling". Cancer Research 69 (14): 5752–60. July 2009. doi:10.1158/0008-5472.CAN-08-3992. PMID 19605405. 
  10. ↑ 10.0 10.1 10.2 10.3 "Attenuation of Forkhead signaling by the retinal determination factor DACH1". Proceedings of the National Academy of Sciences of the United States of America 107 (15): 6864–9. April 2010. doi:10.1073/pnas.1002746107. PMID 20351289. Bibcode: 2010PNAS..107.6864Z. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 "Cell fate factor DACH1 represses YB-1-mediated oncogenic transcription and translation". Cancer Research 74 (3): 829–39. February 2014. doi:10.1158/0008-5472.CAN-13-2466. PMID 24335958. 
  12. ↑ "Transcription elongation regulator 1 is a co-integrator of the cell fate determination factor Dachshund homolog 1". The Journal of Biological Chemistry 285 (51): 40342–50. December 2010. doi:10.1074/jbc.M110.156141. PMID 20956529. 
  13. ↑ 13.0 13.1 13.2 "Master regulators in development: Views from the Drosophila retinal determination and mammalian pluripotency gene networks". Developmental Biology 421 (2): 93–107. January 2017. doi:10.1016/j.ydbio.2016.12.005. PMID 27979656. 
  14. ↑ 14.0 14.1 14.2 "The Dachshund gene in development and hormone-responsive tumorigenesis". Trends in Endocrinology and Metabolism 21 (1): 41–9. January 2010. doi:10.1016/j.tem.2009.08.002. PMID 19896866. 
  15. ↑ "DACH1 negatively regulates the human RANK ligand gene expression in stromal/preosteoblast cells". Journal of Cellular Biochemistry 103 (6): 1747–59. April 2008. doi:10.1002/jcb.21561. PMID 17891780. 
  16. ↑ "Human (DACH) and mouse (Dach) homologues of Drosophila dachshund map to chromosomes 13q22 and 14E3, respectively". Genomics 55 (2): 252–3. January 1999. doi:10.1006/geno.1998.5662. PMID 9933575. 
  17. ↑ 17.0 17.1 "Acetylation of the cell-fate factor dachshund determines p53 binding and signaling modules in breast cancer". Oncotarget 4 (6): 923–35. June 2013. doi:10.18632/oncotarget.1094. PMID 23798621. 
  18. ↑ "Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance". Cell Reports 15 (10): 2214–2225. June 2016. doi:10.1016/j.celrep.2016.05.006. PMID 27239042. 
  19. ↑ 19.0 19.1 19.2 "DACH1 stimulates shear stress-guided endothelial cell migration and coronary artery growth through the CXCL12-CXCR4 signaling axis". Genes & Development 31 (13): 1308–1324. August 2017. doi:10.1101/gad.301549.117. PMID 28779009. 
  20. ↑ "DACH1 - Dachshund homolog 1 - Homo sapiens (Human) - DACH1 gene & protein". https://www.uniprot.org/uniprot/Q9UI36#structure. 
  21. ↑ "DACH1 is a cell fate determination factor that inhibits cyclin D1 and breast tumor growth". Molecular and Cellular Biology 26 (19): 7116–29. October 2006. doi:10.1128/MCB.00268-06. PMID 16980615. 
  22. ↑ 22.0 22.1 "Tissue-specific regulation of retinal and pituitary precursor cell proliferation". Science 297 (5584): 1180–3. August 2002. doi:10.1126/science.1073263. PMID 12130660. 
  23. ↑ 23.0 23.1 "The endogenous cell-fate factor dachshund restrains prostate epithelial cell migration via repression of cytokine secretion via a cxcl signaling module". Cancer Research 75 (10): 1992–2004. May 2015. doi:10.1158/0008-5472.CAN-14-0611. PMID 25769723. 
  24. ↑ 24.0 24.1 "Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8". Proceedings of the National Academy of Sciences of the United States of America 105 (19): 6924–9. May 2008. doi:10.1073/pnas.0802085105. PMID 18467491. Bibcode: 2008PNAS..105.6924W. 
  25. ↑ Watanabe, Akira; Ogiwara, Hideki; Ehata, Shogo; Mukasa, Akitake; Ishikawa, Shumpei; Maeda, Daichi; Ueki, Keisuke; Ino, Yasushi et al. (2011-07-26). "Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells". Proceedings of the National Academy of Sciences of the United States of America 108 (30): 12384–12389. doi:10.1073/pnas.0906930108. ISSN 0027-8424. PMID 21750150. Bibcode: 2011PNAS..10812384W. 
  26. ↑ "Double homozygous missense mutations in DACH1 and BMP4 in a patient with bilateral cystic renal dysplasia". Nephrology, Dialysis, Transplantation 28 (1): 227–32. January 2013. doi:10.1093/ndt/gfs539. PMID 23262432. 

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