DACH1
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Dachshund homolog 1, also known as DACH1, is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
which in humans is encoded by the ''DACH1''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. DACH1 has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...
with Ubc9, Smad4, and NCoR.


Structure


Gene structure

This
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
coding
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
has 760
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
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
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
s. This gene is located, in humans, in
chromosome 13 Chromosome 13 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 13 spans about 113 million base pairs (the building material of DNA) and represents between 3.5 and 4% of the total DNA i ...
(13q22). It encodes a
chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...
-associated protein that associates with other DNA-binding
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s to regulate gene expression, mRNA translation, coactivator binding, and
cell Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...
fate determination during development. Multiple transcript variants encoding different
isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
have been found for this gene. Four
alternatively spliced Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...
transcripts encoding different isoforms have been described for this gene.DACH1
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
was detected in multiple human tissues, including
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
and
heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
. Dach1 is located in nuclear and cytoplasmic pools and is considered a cell fate determination factor. 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
oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
s, which form an α/β structure similar to that found in the winged helix/forkhead subgroup of DNA binding proteins. This protein is widely expressed including
bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
, brain, colon, eye, heart, kidney,
leucocyte White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
, liver, lung, pancreas,
pineal gland The pineal gland (also known as the pineal body or epiphysis cerebri) is a small endocrine gland in the brain of most vertebrates. It produces melatonin, a serotonin-derived hormone, which modulates sleep, sleep patterns following the diurnal c ...
, placenta, prostate, retina, skeletal muscle, small intestine, stromal/preosteoblasts and the spleen.


Protein modification

DACH1 is modified by phosphorylation, acetylation, and SUMOYlation. 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. SUMOYlation of DACH governs HDAC binding. Phosphorylation of Dach1 contributes to YB-1 binding, subcellular distribution and the induction of EMT via translation of EMT regulatory genes.


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. Dach is a member of the Ski gene family and is involved in eye and organismal development. 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 Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...
in
retinal Retinal (also known as retinaldehyde) is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision). Some microorganisms use ret ...
and
pituitary The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus control much of th ...
.


Restrain of cancer cell growth

DACH1
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
is able to prevent the proliferation of cancerous
cells Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a d ...
(lung, breast, prostate) and functions as a repressor of estrogen receptor activity in breast cancer cells.


Transcription

DACH1 conducts transcriptional function through interacting with transcription factors including c-Jun, estrogen receptor alpha, the androgen receptor, 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. Dach1 governs mRNA translation of an EMT signature and governs Snail1 transcription.


Cell migration

DACH1 inhibits migration of vascular endothelial cells, fibroblasts and prostate epithelial cells 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, lung, prostate and brain tumors. DACH1 inhibits
Cyclin D1 Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene. Gene expression The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lo ...
expression and thereby reduces breast cancer cell line cell growth. Normal cells and some breast cancer cells have receptors that bind
estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
and
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
. These two hormones often promote the growth of breast cancer cells. Approximately 70% of breast cancers are
ERa+ Adjusted ERA+, often simply abbreviated to ERA+ or ERA plus, is a pitching statistic in baseball. It adjusts a pitcher's earned run average (ERA) according to the pitcher's ballpark (in case the ballpark favors batters or pitchers) and the ERA o ...
, DACH1 expression decreases when the cancer is more invasive and the level of
estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
is high.


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. Functional analysis of the DACH1 mutation (p.R684C). demonstrated enhanced suppression of the TGF-β pathway. Dach1 is highly expressed in the adult
podocyte Podocytes are cells in Bowman's capsule in the kidneys that wrap around capillaries of the glomerulus. Podocytes make up the epithelial lining of Bowman's capsule, the third layer through which filtration of blood takes place. Bowman's capsule ...
, 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.


References


Further reading

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