Achaete-scute homolog 1 is aprotein that in humans is encoded by theASCL1gene.[5][6] Because it was discovered subsequent to studies on its homolog inDrosophila, theAchaete-scute complex, it was originally named MASH-1 for mammalian achaete scute homolog-1.[7]
Thisgene encodes a member of thebasic helix-loop-helix (BHLH) family of transcription factors. The protein activates transcription by binding to theE box (5'-CANNTG-3').Dimerization with other BHLH proteins is required for efficientDNA binding. This protein plays a role in the neuronal commitment and differentiation and in the generation of olfactory and autonomicneurons. It is highly expressed inmedullary thyroid cancer andsmall 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.[6]
Development of the vertebrate nervous system begins when theneural tube forms in the earlyembryo. The neural tube eventually gives rise to the entirenervous system, but firstneuroblasts must differentiate from theneuroepithelium of the tube. The neuroblasts are the cells that undergomitotic division and produceneurons.[7] Asc is central to the differentiation of the neuroblasts and thelateral inhibition mechanism which inherently creates a safety net in the event of damage or death in these incredibly important cells.[7]
Differentiation of the neuroblast begins when the cells of the neural tube express Asc and thus upregulate the expression ofDelta, a protein essential to the lateral inhibition pathway of neuronal commitment.[7] Delta, a membrane-bound protein, can then bind to theNotch receptor of neighbouring cells, which upon activation undergoesproteolytic cleavage to release the intracellular domain (Notch-ICD).[7] The Notch-ICD is then free to travel to the nucleus and form a complex with Suppressor ofHairless (SuH) andMastermind.[7] This complex, by inducing the transcription of HES1, a transcriptional repressor, then represses the transcription of Asc and accomplishes two important tasks. First, it prevents the expression of factors required for differentiation of the cell into a neuroblast.[7] Secondly, it inhibits the neighboring cell's production of Delta.[7] 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.[7]This process of neuroblast differentiation via Asc is common to all animals.[7] Although this mechanism was initially studied in Drosophila, homologs to all proteins in the pathway have been found in vertebrates that have the samebHLH structure.[7]
In addition to its important role in neuroblast formation, Asc also functions to mediateautonomic nervous system (ANS) formation.[8] Asc was initially suspected to play a role in the ANS when ASCL1 was found expressed in cells surrounding the dorsalaorta, theadrenal glands and in the developingsympathetic chain during a specific stage of development.[8] Subsequent studies of mice genetically altered to be MASH-1 deficient revealed defective development of both sympathetic and parasympatheticganglia, the two constituents of the ANS.[8]
^abcAxelson H (February 2004). "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.doi:10.1016/s0304-3835(03)00453-1.PMID15013216.
Chen H, Kunnimalaiyaan M, Van Gompel JJ (June 2005). "Medullary thyroid cancer: the functions of raf-1 and human achaete-scute homologue-1".Thyroid.15 (6):511–21.doi:10.1089/thy.2005.15.511.PMID16029117.
Borges M, Linnoila RI, van de Velde HJ, Chen H, Nelkin BD, Mabry M, et al. (April 1997). "An achaete-scute homologue essential for neuroendocrine differentiation in the lung".Nature.386 (6627):852–5.Bibcode:1997Natur.386..852B.doi:10.1038/386852a0.PMID9126746.S2CID4336900.
Chen H, Biel MA, Borges MW, Thiagalingam A, Nelkin BD, Baylin SB, et al. (June 1997). "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.PMID9186001.
Rozovskaia T, Rozenblatt-Rosen O, Sedkov Y, Burakov D, Yano T, Nakamura T, et al. (January 2000). "Self-association of the SET domains of human ALL-1 and of Drosophila TRITHORAX and ASH1 proteins".Oncogene.19 (3):351–7.doi:10.1038/sj.onc.1203307.PMID10656681.S2CID43415797.
Persson P, Jögi A, Grynfeld A, Påhlman S, Axelson H (July 2000). "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.Bibcode:2000BBRC..274...22P.doi:10.1006/bbrc.2000.3090.PMID10903890.
Westerman BA, Neijenhuis S, Poutsma A, Steenbergen RD, Breuer RH, Egging M, et al. (April 2002). "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.PMID11948117.
Sippel RS, Carpenter JE, Kunnimalaiyaan M, Chen H (December 2003). "The role of human achaete-scute homolog-1 in medullary thyroid cancer cells".Surgery.134 (6):866–71, discussion 871-3.doi:10.1016/s0039-6060(03)00418-5.PMID14668716.
Ferretti E, Di Stefano D, Zazzeroni F, Gallo R, Fratticci A, Carfagnini R, et al. (October 2003). "Human pituitary tumours express the bHLH transcription factors NeuroD1 and ASH1".Journal of Endocrinological Investigation.26 (10):957–65.doi:10.1007/bf03348192.PMID14759067.S2CID7358739.
