Dachshund homolog 1, also known as DACH1, is a protein which in humans is encoded by the DACH1gene.[5][6][7] DACH1 has been shown to interact with Ubc9,[8] Smad4,[9] and NCoR.[9][10]
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.[17][18] 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.[14] 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.[10][19][20]
Protein modification
DACH1 is modified by phosphorylation,[15] acetylation,[21] and SUMOYlation.[22] 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.[21] SUMOYlation of DACH governs HDAC binding.[23] Phosphorylation of Dach1 contributes to YB-1 binding, subcellular distribution and the induction of EMT via translation of EMT regulatory genes.[15]
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.[6] Dach is a member of the Ski gene family and is involved in eye and organismal development.[18][25] 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.[7][17][26]
Restrain of cancer cell growth
DACH1 protein is able to prevent the proliferation of cancerous cells (lung, breast, prostate[11][12][10][13][14]) and functions as a repressor of estrogen receptor activity in breast cancer cells.[11][13]
Transcription
DACH1 conducts transcriptional function through interacting with transcription factors including c-Jun,[11] estrogen receptor alpha,[13] the androgen receptor,[10] 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.[14] Dach1 governs mRNA translation of an EMT signature[15] and governs Snail1 transcription.[15]
Cell migration
DACH1 inhibits migration of vascular endothelial cells,[23][27] fibroblasts[28] and prostate epithelial cells[27] 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 putative 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,[26][15] lung,[12] prostate[10] and brain tumors.[29] DACH1 inhibits Cyclin D1 expression and thereby reduces breast cancer cell line cell growth.[28] 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.[13]
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.[30] 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.[23]
^ abMardon G, Solomon NM, Rubin GM (December 1994). "dachshund encodes a nuclear protein required for normal eye and leg development in Drosophila". Development. 120 (12): 3473–86. doi:10.1242/dev.120.12.3473. PMID7821215.
^ abShen W, Mardon G (January 1997). "Ectopic eye development in Drosophila induced by directed dachshund expression". Development. 124 (1): 45–52. doi:10.1242/dev.124.1.45. PMID9006066.
^Hammond KL, Lettice LA, Hill RE, Lee M, Boyle S, Hanson IM (January 1999). "Human (DACH) and mouse (Dach) homologues of Drosophila dachshund map to chromosomes 13q22 and 14E3, respectively". Genomics. 55 (2): 252–3. doi:10.1006/geno.1998.5662. PMID9933575.
Hammond KL, Lettice LA, Hill RE, Lee M, Boyle S, Hanson IM (1999). "Human (DACH) and mouse (Dach) homologues of Drosophila dachshund map to chromosomes 13q22 and 14E3, respectively". Genomics. 55 (2): 252–253. doi:10.1006/geno.1998.5662. PMID9933575.
Kozmik Z, Cvekl A (1999). "Localization of the human homologue of the Drosophila dachshund gene (DACH) to chromosome 13q21". Genomics. 59 (1): 110–111. doi:10.1006/geno.1999.5797. PMID10395809.
Kozmik Z, Pfeffer P, Kralova J, Paces J, Paces V, Kalousova A, Cvekl A (1999). "Molecular cloning and expression of the human and mouse homologues of the Drosophila dachshund gene". Dev. Genes Evol. 209 (9): 537–545. doi:10.1007/s004270050286. PMID10502110. S2CID6814864.
Li X, Oghi KA, Zhang J, Krones A, Bush KT, Glass CK, Nigam SK, Aggarwal AK, Maas R, Rose DW, Rosenfeld MG (2003). "Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis". Nature. 426 (6964): 247–254. Bibcode:2003Natur.426..247L. doi:10.1038/nature02083. PMID14628042. S2CID4348941.
Martini SR, Davis RL (2005). "The dachshund gene is required for the proper guidance and branching of mushroom body axons in Drosophila melanogaster". J. Neurobiol. 64 (2): 133–144. doi:10.1002/neu.20130. PMID15818552.
