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Ascl1

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Ascl1

Achaete-scute family bHLH transcription factor 1
Identifiers
Symbols  ; ASH1; HASH1; MASH1; bHLHa46
External IDs GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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] 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]

Contents

  • Role in neuronal commitment 1
  • Autonomic nervous system development 2
  • Interactions 3
  • References 4
  • Further reading 5
  • External links 6

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

  1. ^ Ball DW, Azzoli CG, Baylin SB, Chi D, Dou S, Donis-Keller H, Cumaraswamy A, Borges M, Nelkin BD (Jul 1993). "Identification of a human achaete-scute homolog highly expressed in neuroendocrine tumors". Proc Natl Acad Sci U S A 90 (12): 5648–52.  
  2. ^ a b "Entrez Gene: ASCL1 achaete-scute complex homolog 1 (Drosophila)". 
  3. ^ a b c d e f g h i j k Sanes, Dan Harvey (2011). The development of the nervous system. Elsevier.  
  4. ^ a b c Axelson, H (20 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.  
  5. ^ Mao, Z; Nadal-Ginard B (Jun 1996). "Functional and physical interactions between mammalian achaete-scute homolog 1 and myocyte enhancer factor 2A". J. Biol. Chem. (UNITED STATES) 271 (24): 14371–5.  

Further reading

  • Chen H, Kunnimalaiyaan M, Van Gompel JJ (2006). "Medullary thyroid cancer: the functions of raf-1 and human achaete-scute homologue-1". Thyroid 15 (6): 511–21.  
  • Renault B, Lieman J, Ward D, et al. (1996). "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.  
  • Mao Z, Nadal-Ginard B (1996). "Functional and physical interactions between mammalian achaete-scute homolog 1 and myocyte enhancer factor 2A". J. Biol. Chem. 271 (24): 14371–5.  
  • Borges M, Linnoila RI, van de Velde HJ, et al. (1997). "An achaete-scute homologue essential for neuroendocrine differentiation in the lung". Nature 386 (6627): 852–5.  
  • Chen H, Biel MA, Borges MW, et al. (1997). "Tissue-specific expression of human achaete-scute homologue-1 in neuroendocrine tumors: transcriptional regulation by dual inhibitory regions". Cell Growth Differ. 8 (6): 677–86.  
  • Lo L, Sommer L, Anderson DJ (1997). "MASH1 maintains competence for BMP2-induced neuronal differentiation in post-migratory neural crest cells". Curr. Biol. 7 (6): 440–50.  
  • Rozovskaia T, Rozenblatt-Rosen O, Sedkov Y, et al. (2000). "Self-association of the SET domains of human ALL-1 and of Drosophila TRITHORAX and ASH1 proteins". Oncogene 19 (3): 351–7.  
  • Persson P, Jögi A, Grynfeld A, et al. (2000). "HASH-1 and E2-2 are expressed in human neuroblastoma cells and form a functional complex". Biochem. Biophys. Res. Commun. 274 (1): 22–31.  
  • Maxon ME, Herskowitz I (2001). "Ash1p is a site-specific DNA-binding protein that actively represses transcription". Proc. Natl. Acad. Sci. U.S.A. 98 (4): 1495–500.  
  • Long RM, Gu W, Meng X, et al. (2001). "An exclusively nuclear RNA-binding protein affects asymmetric localization of ASH1 mRNA and Ash1p in yeast". J. Cell Biol. 153 (2): 307–18.  
  • Parras CM, Schuurmans C, Scardigli R, et al. (2002). "Divergent functions of the proneural genes Mash1 and Ngn2 in the specification of neuronal subtype identity". Genes Dev. 16 (3): 324–38.  
  • Sriuranpong V, Borges MW, Strock CL, et al. (2002). "Notch signaling induces rapid degradation of achaete-scute homolog 1". Mol. Cell. Biol. 22 (9): 3129–39.  
  • Westerman BA, Neijenhuis S, Poutsma A, et al. (2002). "Quantitative reverse transcription-polymerase chain reaction measurement of HASH1 (ASCL1), a marker for small cell lung carcinomas with neuroendocrine features". Clin. Cancer Res. 8 (4): 1082–6.  
  • Letinic K, Zoncu R, Rakic P (2002). "Origin of GABAergic neurons in the human neocortex". Nature 417 (6889): 645–9.  
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903.  
  • de Pontual L, Népote V, Attié-Bitach T, et al. (2004). "Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse)". Hum. Mol. Genet. 12 (23): 3173–80.  
  • Sippel RS, Carpenter JE, Kunnimalaiyaan M, Chen H (2004). "The role of human achaete-scute homolog-1 in medullary thyroid cancer cells". Surgery 134 (6): 866–71; discussion 871–3.  
  • Ferretti E, Di Stefano D, Zazzeroni F, et al. (2004). "Human pituitary tumours express the bHLH transcription factors NeuroD1 and ASH1". J. Endocrinol. Invest. 26 (10): 957–65.  
  • Mhawech P, Berczy M, Assaly M, et al. (2004). "Human achaete-scute homologue (hASH1) mRNA level as a diagnostic marker to distinguish esthesioneuroblastoma from poorly differentiated tumors arising in the sinonasal tract". Am. J. Clin. Pathol. 122 (1): 100–5.  

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


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