“ASCL1”的意思、由来-开放百科全书

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

References

1. ^{{cite journal | vauthors = Ball DW, Azzoli CG, Baylin SB, Chi D, Dou S, Donis-Keller H, Cumaraswamy A, Borges M, Nelkin BD | title = Identification of a human achaete-scute homolog highly expressed in neuroendocrine tumors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 12 | pages = 5648–52 | date = Jun 1993 | pmid = 8390674 | pmc = 46778 | doi = 10.1073/pnas.90.12.5648 }}
2. ^¹{{cite web | title = Entrez Gene: ASCL1 achaete-scute complex homolog 1 (Drosophila)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=429| accessdate = }}
3. ^¹²³⁴⁵⁶⁷⁸⁹¹⁰{{cite book|last=Sanes|first=Dan Harvey|title=The development of the nervous system|year=2011|publisher=Elsevier|isbn=978-0-12-374539-2}}
4. ^¹²{{cite journal | vauthors = Axelson H | title = The Notch signaling cascade in neuroblastoma: role of the basic helix-loop-helix proteins HASH-1 and HES-1 | journal = Cancer Letters | volume = 204 | issue = 2 | pages = 171–8 | date = Feb 2004 | pmid = 15013216 | doi = 10.1016/s0304-3835(03)00453-1 }}
5. ^{{cite journal | vauthors = Mao Z, Nadal-Ginard B | title = Functional and physical interactions between mammalian achaete-scute homolog 1 and myocyte enhancer factor 2A | journal = The Journal of Biological Chemistry | volume = 271 | issue = 24 | pages = 14371–5 | date = Jun 1996 | pmid = 8662987 | doi = 10.1074/jbc.271.24.14371 }}

Further reading

{{cite journal | vauthors = Chen H, Kunnimalaiyaan M, Van Gompel JJ | title = Medullary thyroid cancer: the functions of raf-1 and human achaete-scute homologue-1 | journal = Thyroid | volume = 15 | issue = 6 | pages = 511–21 | date = Jun 2005 | pmid = 16029117 | doi = 10.1089/thy.2005.15.511 }}

{{cite journal | vauthors = Renault B, Lieman J, Ward D, Krauter K, Kucherlapati R | title = 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 | journal = Genomics | volume = 30 | issue = 1 | pages = 81–3 | date = Nov 1995 | pmid = 8595908 | doi = 10.1006/geno.1995.0012 }}

{{cite journal | vauthors = Mao Z, Nadal-Ginard B | title = Functional and physical interactions between mammalian achaete-scute homolog 1 and myocyte enhancer factor 2A | journal = The Journal of Biological Chemistry | volume = 271 | issue = 24 | pages = 14371–5 | date = Jun 1996 | pmid = 8662987 | doi = 10.1074/jbc.271.24.14371 }}

{{cite journal | vauthors = Borges M, Linnoila RI, van de Velde HJ, Chen H, Nelkin BD, Mabry M, Baylin SB, Ball DW | title = An achaete-scute homologue essential for neuroendocrine differentiation in the lung | journal = Nature | volume = 386 | issue = 6627 | pages = 852–5 | date = Apr 1997 | pmid = 9126746 | doi = 10.1038/386852a0 }}

{{cite journal | vauthors = Chen H, Biel MA, Borges MW, Thiagalingam A, Nelkin BD, Baylin SB, Ball DW | title = Tissue-specific expression of human achaete-scute homologue-1 in neuroendocrine tumors: transcriptional regulation by dual inhibitory regions | journal = Cell Growth & Differentiation | volume = 8 | issue = 6 | pages = 677–86 | date = Jun 1997 | pmid = 9186001 | doi = }}

{{cite journal | vauthors = Lo L, Sommer L, Anderson DJ | title = MASH1 maintains competence for BMP2-induced neuronal differentiation in post-migratory neural crest cells | journal = Current Biology | volume = 7 | issue = 6 | pages = 440–50 | date = Jun 1997 | pmid = 9197246 | doi = 10.1016/S0960-9822(06)00191-6 }}

{{cite journal | vauthors = Rozovskaia T, Rozenblatt-Rosen O, Sedkov Y, Burakov D, Yano T, Nakamura T, Petruck S, Ben-Simchon L, Croce CM, Mazo A, Canaani E | title = Self-association of the SET domains of human ALL-1 and of Drosophila TRITHORAX and ASH1 proteins | journal = Oncogene | volume = 19 | issue = 3 | pages = 351–7 | date = Jan 2000 | pmid = 10656681 | doi = 10.1038/sj.onc.1203307 }}

{{cite journal | vauthors = Persson P, Jögi A, Grynfeld A, Påhlman S, Axelson H | title = HASH-1 and E2-2 are expressed in human neuroblastoma cells and form a functional complex | journal = Biochemical and Biophysical Research Communications | volume = 274 | issue = 1 | pages = 22–31 | date = Jul 2000 | pmid = 10903890 | doi = 10.1006/bbrc.2000.3090 }}

{{cite journal | vauthors = Maxon ME, Herskowitz I | title = Ash1p is a site-specific DNA-binding protein that actively represses transcription | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 4 | pages = 1495–500 | date = Feb 2001 | pmid = 11171979 | pmc = 29285 | doi = 10.1073/pnas.98.4.1495 }}

{{cite journal | vauthors = Long RM, Gu W, Meng X, Gonsalvez G, Singer RH, Chartrand P | title = An exclusively nuclear RNA-binding protein affects asymmetric localization of ASH1 mRNA and Ash1p in yeast | journal = The Journal of Cell Biology | volume = 153 | issue = 2 | pages = 307–18 | date = Apr 2001 | pmid = 11309412 | pmc = 2169461 | doi = 10.1083/jcb.153.2.307 }}

{{cite journal | vauthors = Parras CM, Schuurmans C, Scardigli R, Kim J, Anderson DJ, Guillemot F | title = Divergent functions of the proneural genes Mash1 and Ngn2 in the specification of neuronal subtype identity | journal = Genes & Development | volume = 16 | issue = 3 | pages = 324–38 | date = Feb 2002 | pmid = 11825874 | pmc = 155336 | doi = 10.1101/gad.940902 }}

{{cite journal | vauthors = Sriuranpong V, Borges MW, Strock CL, Nakakura EK, Watkins DN, Blaumueller CM, Nelkin BD, Ball DW | title = Notch signaling induces rapid degradation of achaete-scute homolog 1 | journal = Molecular and Cellular Biology | volume = 22 | issue = 9 | pages = 3129–39 | date = May 2002 | pmid = 11940670 | pmc = 133746 | doi = 10.1128/MCB.22.9.3129-3139.2002 }}

{{cite journal | vauthors = Westerman BA, Neijenhuis S, Poutsma A, Steenbergen RD, Breuer RH, Egging M, van Wijk IJ, Oudejans CB | title = Quantitative reverse transcription-polymerase chain reaction measurement of HASH1 (ASCL1), a marker for small cell lung carcinomas with neuroendocrine features | journal = Clinical Cancer Research | volume = 8 | issue = 4 | pages = 1082–6 | date = Apr 2002 | pmid = 11948117 | doi = }}

{{cite journal | vauthors = Letinic K, Zoncu R, Rakic P | title = Origin of GABAergic neurons in the human neocortex | journal = Nature | volume = 417 | issue = 6889 | pages = 645–9 | date = Jun 2002 | pmid = 12050665 | doi = 10.1038/nature00779 }}

{{cite journal | vauthors = de Pontual L, Népote V, Attié-Bitach T, Al Halabiah H, Trang H, Elghouzzi V, Levacher B, Benihoud K, Augé J, Faure C, Laudier B, Vekemans M, Munnich A, Perricaudet M, Guillemot F, Gaultier C, Lyonnet S, Simonneau M, Amiel J | title = Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse) | journal = Human Molecular Genetics | volume = 12 | issue = 23 | pages = 3173–80 | date = Dec 2003 | pmid = 14532329 | doi = 10.1093/hmg/ddg339 }}

{{cite journal | vauthors = Sippel RS, Carpenter JE, Kunnimalaiyaan M, Chen H | title = The role of human achaete-scute homolog-1 in medullary thyroid cancer cells | journal = Surgery | volume = 134 | issue = 6 | pages = 866–71; discussion 871–3 | date = Dec 2003 | pmid = 14668716 | doi = 10.1016/s0039-6060(03)00418-5}}

{{cite journal | vauthors = Ferretti E, Di Stefano D, Zazzeroni F, Gallo R, Fratticci A, Carfagnini R, Angiulli S, Santoro A, Minniti G, Tamburrano G, Alesse E, Cantore G, Gulino A, Jaffrain-Rea ML | title = Human pituitary tumours express the bHLH transcription factors NeuroD1 and ASH1 | journal = Journal of Endocrinological Investigation | volume = 26 | issue = 10 | pages = 957–65 | date = Oct 2003 | pmid = 14759067 | doi = 10.1007/bf03348192 }}

{{cite journal | vauthors = Mhawech P, Berczy M, Assaly M, Herrmann F, Bouzourene H, Allal AS, Dulguerov P, Schwaller J | title = Human achaete-scute homologue (hASH1) mRNA level as a diagnostic marker to distinguish esthesioneuroblastoma from poorly differentiated tumors arising in the sinonasal tract | journal = American Journal of Clinical Pathology | volume = 122 | issue = 1 | pages = 100–5 | date = Jul 2004 | pmid = 15272537 | doi = 10.1309/QD0K-9Q1J-BH6B-5GQQ | url = https://archive-ouverte.unige.ch/unige:25899/ATTACHMENT01 }}

Function

Role in neuronal commitment

Autonomic nervous system development

Interactions

References

Further reading

External links