Biology:ASCL1
Generic protein structure example |
Achaete-scute homolog 1 is a protein that in humans is encoded by the ASCL1 gene.[1][2] Because it was discovered subsequent to studies on its homolog in Drosophila, the Achaete-scute complex, it was originally named MASH-1 for mammalian achaete scute homolog-1.[3]
Function
This gene encodes a member of the basic helix-loop-helix (BHLH) family of transcription factors. The protein activates transcription by binding to the E box (5'-CANNTG-3'). Dimerization with other BHLH proteins is required for efficient DNA binding. This protein plays a role in the neuronal commitment and differentiation and in the generation of olfactory and autonomic neurons. It is highly expressed in medullary thyroid cancer and small cell lung cancer and may be a useful marker for these cancers. The presence of a CAG repeat in the gene suggests that it may also play a role in tumor formation.[2]
Role in neuronal commitment
Development of the vertebrate nervous system begins when the neural tube forms in the early embryo. The neural tube eventually gives rise to the entire nervous system, but first neuroblasts must differentiate from the neuroepithelium of the tube. The neuroblasts are the cells that undergo mitotic division and produce neurons.[3] Asc is central to the differentiation of the neuroblasts and the lateral inhibition mechanism which inherently creates a safety net in the event of damage or death in these incredibly important cells.[3]
Differentiation of the neuroblast begins when the cells of the neural tube express Asc and thus upregulate the expression of Delta, a protein essential to the lateral inhibition pathway of neuronal commitment.[3] Delta can diffuse to neighboring cells and bind to the Notch receptor, a large transmembrane protein which upon activation undergoes proteolytic cleavage to release the intracellular domain (Notch-ICD).[3] The Notch-ICD is then free to travel to the nucleus and form a complex with Suppressor of Hairless (SuH) and Mastermind.[3] This complex acts as transcription regulator of Asc and accomplishes two important tasks. First, it prevents the expression of factors required for differentiation of the cell into a neuroblast.[3] Secondly, it inhibits the neighboring cell's production of Delta.[3] Therefore, the future neuroblast will be the cell that has the greatest Asc activation in the vicinity and consequently the greatest Delta production that will inhibit the differentiation of neighboring cells. The select group of neuroblasts that then differentiate in the neural tube are thus replaceable because the neuroblast's ability to suppress differentiation of neighboring cells depends on its own ability to produce Asc.[3] This process of neuroblast differentiation via Asc is common to all animals.[3] Although this mechanism was initially studied in Drosophila, homologs to all proteins in the pathway have been found in vertebrates that have the same bHLH structure.[3]
Autonomic nervous system development
In addition to its important role in neuroblast formation, Asc also functions to mediate autonomic nervous system (ANS) formation.[4] Asc was initially suspected to play a role in the ANS when ASCL1 was found expressed in cells surrounding the dorsal aorta, the adrenal glands and in the developing sympathetic chain during a specific stage of development.[4] Subsequent studies of mice genetically altered to be MASH-1 deficient revealed defective development of both sympathetic and parasympathetic ganglia, the two constituents of the ANS.[4]
Interactions
ASCL1 has been shown to interact with Myocyte-specific enhancer factor 2A.[5]
References
- ↑ "Identification of a human achaete-scute homolog highly expressed in neuroendocrine tumors". Proceedings of the National Academy of Sciences of the United States of America 90 (12): 5648–52. June 1993. doi:10.1073/pnas.90.12.5648. PMID 8390674. Bibcode: 1993PNAS...90.5648B.
- ↑ 2.0 2.1 "Entrez Gene: ASCL1 achaete-scute complex homolog 1 (Drosophila)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=429.
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 Sanes, Dan Harvey (2011). The development of the nervous system. Elsevier. ISBN 978-0-12-374539-2.
- ↑ 4.0 4.1 4.2 "The Notch signaling cascade in neuroblastoma: role of the basic helix-loop-helix proteins HASH-1 and HES-1". Cancer Letters 204 (2): 171–8. February 2004. doi:10.1016/s0304-3835(03)00453-1. PMID 15013216.
- ↑ "Functional and physical interactions between mammalian achaete-scute homolog 1 and myocyte enhancer factor 2A". The Journal of Biological Chemistry 271 (24): 14371–5. June 1996. doi:10.1074/jbc.271.24.14371. PMID 8662987.
Further reading
- "Medullary thyroid cancer: the functions of raf-1 and human achaete-scute homologue-1". Thyroid 15 (6): 511–21. June 2005. doi:10.1089/thy.2005.15.511. PMID 16029117.
- "Localization of the human achaete-scute homolog gene (ASCL1) distal to phenylalanine hydroxylase (PAH) and proximal to tumor rejection antigen (TRA1) on chromosome 12q22-q23". Genomics 30 (1): 81–3. November 1995. doi:10.1006/geno.1995.0012. PMID 8595908.
- "Functional and physical interactions between mammalian achaete-scute homolog 1 and myocyte enhancer factor 2A". The Journal of Biological Chemistry 271 (24): 14371–5. June 1996. doi:10.1074/jbc.271.24.14371. PMID 8662987.
- "An achaete-scute homologue essential for neuroendocrine differentiation in the lung". Nature 386 (6627): 852–5. April 1997. doi:10.1038/386852a0. PMID 9126746. Bibcode: 1997Natur.386..852B.
- "Tissue-specific expression of human achaete-scute homologue-1 in neuroendocrine tumors: transcriptional regulation by dual inhibitory regions". Cell Growth & Differentiation 8 (6): 677–86. June 1997. PMID 9186001.
- "MASH1 maintains competence for BMP2-induced neuronal differentiation in post-migratory neural crest cells". Current Biology 7 (6): 440–50. June 1997. doi:10.1016/S0960-9822(06)00191-6. PMID 9197246.
- "Self-association of the SET domains of human ALL-1 and of Drosophila TRITHORAX and ASH1 proteins". Oncogene 19 (3): 351–7. January 2000. doi:10.1038/sj.onc.1203307. PMID 10656681.
- "HASH-1 and E2-2 are expressed in human neuroblastoma cells and form a functional complex". Biochemical and Biophysical Research Communications 274 (1): 22–31. July 2000. doi:10.1006/bbrc.2000.3090. PMID 10903890.
- "An exclusively nuclear RNA-binding protein affects asymmetric localization of ASH1 mRNA and Ash1p in yeast". The Journal of Cell Biology 153 (2): 307–18. April 2001. doi:10.1083/jcb.153.2.307. PMID 11309412.
- "Divergent functions of the proneural genes Mash1 and Ngn2 in the specification of neuronal subtype identity". Genes & Development 16 (3): 324–38. February 2002. doi:10.1101/gad.940902. PMID 11825874.
- "Notch signaling induces rapid degradation of achaete-scute homolog 1". Molecular and Cellular Biology 22 (9): 3129–39. May 2002. doi:10.1128/MCB.22.9.3129-3139.2002. PMID 11940670.
- "Quantitative reverse transcription-polymerase chain reaction measurement of HASH1 (ASCL1), a marker for small cell lung carcinomas with neuroendocrine features". Clinical Cancer Research 8 (4): 1082–6. April 2002. PMID 11948117.
- "Origin of GABAergic neurons in the human neocortex". Nature 417 (6889): 645–9. June 2002. doi:10.1038/nature00779. PMID 12050665. Bibcode: 2002Natur.417..645L.
- "Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse)". Human Molecular Genetics 12 (23): 3173–80. December 2003. doi:10.1093/hmg/ddg339. PMID 14532329.
- "The role of human achaete-scute homolog-1 in medullary thyroid cancer cells". Surgery 134 (6): 866–71; discussion 871-3. December 2003. doi:10.1016/s0039-6060(03)00418-5. PMID 14668716.
- "Human pituitary tumours express the bHLH transcription factors NeuroD1 and ASH1". Journal of Endocrinological Investigation 26 (10): 957–65. October 2003. doi:10.1007/bf03348192. PMID 14759067.
- "Human achaete-scute homologue (hASH1) mRNA level as a diagnostic marker to distinguish esthesioneuroblastoma from poorly differentiated tumors arising in the sinonasal tract". American Journal of Clinical Pathology 122 (1): 100–5. July 2004. doi:10.1309/QD0K-9Q1J-BH6B-5GQQ. PMID 15272537. https://archive-ouverte.unige.ch/unige:25899/ATTACHMENT01.
External links
- ASCL1+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
- Human ASCL1 genome location and ASCL1 gene details page in the UCSC Genome Browser.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
Original source: https://en.wikipedia.org/wiki/ASCL1.
Read more |