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Gene Review

ASCL1  -  achaete-scute family bHLH transcription...

Homo sapiens

Synonyms: ASH-1, ASH1, Achaete-scute homolog 1, BHLHA46, Class A basic helix-loop-helix protein 46, ...
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Disease relevance of ASCL1


Psychiatry related information on ASCL1

  • The transition from proliferation to neurogenesis involves a coordinate increase in the activity of proneural bHLH factors (Mash1, Neurogenin1, and Neurogenin2) and a decrease in the activity of Hes and Id factors [6].
  • As Mash and Hunsley (2005) discuss in this special section, evidence-based assessment tools not only demonstrate adequate psychometric qualities, but also have relevance to the delivery of services to individuals with the disorder (see also Hayes, Nelson, & Jarrett, 1987) [7].
  • Examined the convergent and discriminant validity of the Parent Attribution Test (PAT; Bugental, Blue, & Cruzcosa, 1989), the Parental Locus of Control Scale (PLOC; Campis, Lyman, & Prentice-Dunn, 1986), and the Parenting Sense of Competence-Efficacy Scale (PSOC-Efficacy; Johnston & Mash, 1989) in 3 samples of community mothers [8].

High impact information on ASCL1

  • The second lineage, characterized by the expression of Dlx1/2 but not Mash1, forms around 35% of the GABAergic neurons and originates from the ganglionic eminence of the ventral forebrain [9].
  • What are the roles of MASH1 and other regulatory genes in controlling early stages in neural crest cell determination, and how is the expression of these molecules in turn controlled [10]?
  • Using this approach, we demonstrate that Mash1 has the capacity to respecify the identity of neuronal populations normally derived from Ngn2-expressing progenitors in the dorsal telencephalon and ventral spinal cord [11].
  • Thus, Hes5-dependent modulation of myelin gene expression involves old players (i.e. Mash1) and novel mechanisms of transcriptional regulation that include cell-specific regulatory loops with transcriptional activators (i.e. Sox10) [12].
  • Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression [13].

Biological context of ASCL1


Anatomical context of ASCL1


Associations of ASCL1 with chemical compounds

  • The present genetic data may thus suggest that polyglutamine length polymorphisms in ASCL1 could influence predispositions to PD through the fine-tuning of LC integrity [3].
  • Treatment of TT-NOTCH cells with doxycycline led to dose-dependent induction of NOTCH1 protein with corresponding decreases in ASCL1 protein and NE hormones [17].
  • Further, TT cells were treated with nontoxic concentrations of LY294002 for 2 days, and Western blot analyses were performed for phospho-Akt, total Akt, and the NE tumor markers CgA and human achaete-scute homolog1 (ASCL1) [18].
  • Differential actions of the proneural genes encoding Mash1 and neurogenins in Nurr1-induced dopamine neuron differentiation [19].
  • Furthermore, a demethylating agent, 5-aza-2'-deoxycytidine, reactivated the ASCL expression in the methylation-silenced cells, indicating that ASCL is silenced by the associated DNA methylation [20].

Physical interactions of ASCL1

  • The HASH-1/E2-2 complex binds an E-box (CACCTG) in vitro, and transactivates an E-box containing reporter construct in vivo [4].

Regulatory relationships of ASCL1

  • Conversely, null mutation of HES1 up-regulates Mash1 expression, accelerates neuronal differentiation, and causes severe defects of the brain and eyes [21].
  • The expression of HASH-1 was also up-regulated by IFN-gamma [22].
  • Conversely, Mash1 induces neuronal differentiation characterized by the expression of generic neuronal genes SCG10, Hu and NF160; however, only a subpopulation of these neurons also displays an autonomic, noradrenergic phenotype [23].

Other interactions of ASCL1

  • The deletion of the PAH, IGF1, and ASCL1 genes could explain the patient's phenotype corresponding to a contiguous gene syndrome [24].
  • Logistic regression analysis revealed the effect of ASCL1 dominant x PHOX2B additive (P=0.008) as an epistatic gene-gene interaction increasing risk of PD [3].
  • When neuroblastoma cells are induced to differentiate, as indicated by neuronal morphology and upregulation of neuronal marker genes, the HASH-1 expression is rapidly downregulated with a concomitant, transient upregulation of HES-1 [15].
  • Prolactin and ACTH tumors had the highest levels of expression of hASH-1 [25].
  • Domain-swapping experiments with Mash1 and NeuroD indicated that the helix-loop-helix domain, responsible for mediating dimerization of bHLH transcription factors, imparts the distinct effect [19].

Analytical, diagnostic and therapeutic context of ASCL1

  • By real-time RT-PCR, the amounts of hASH1 mRNA in a small cell NEC were 16,600 times higher than those in adenocarcinomas and 110 times higher than those in a carcinoid tumor [26].
  • Dual promoters initiate hASH1 transcription, with the predominant site being an evolutionarily conserved initiator (INR) element [27].
  • On transplantation into the striatum of Parkinsonian rats, precursor cells engineered with Nurr1/SHH/Bcl-XL or Nurr1/Mash1 survived in vivo and differentiated into mature DA neurons that can reverse the behavioral deficits in the grafted animals [28].
  • Furthermore, manipulation of the BMP signaling pathway in vivo via electroporation of expression vectors encoding either BMP or NOGGIN coupled with MASH1 gain-of-function experiments demonstrate that a BMP-mediated transcriptional cascade involving Cash1 and Tlx-3 specifies first-order relay sensory neurons in the developing brainstem [29].
  • Sequence alignment of the predicted amino acid sequence of Fash1 with other vertebrate homologs of the achaete scute homolog 1 subclass shows that the carboxyl 2/3 of the protein, including the basic helix-loop-helix, a putative nuclear localization signal and several consensus phosphorylation sites, is highly conserved [30].


  1. Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma. Somasundaram, K., Reddy, S.P., Vinnakota, K., Britto, R., Subbarayan, M., Nambiar, S., Hebbar, A., Samuel, C., Shetty, M., Sreepathi, H.K., Santosh, V., Hegde, A.S., Hegde, S., Kondaiah, P., Rao, M.R. Oncogene (2005) [Pubmed]
  2. Quantitative reverse transcription-polymerase chain reaction measurement of HASH1 (ASCL1), a marker for small cell lung carcinomas with neuroendocrine features. Westerman, B.A., Neijenhuis, S., Poutsma, A., Steenbergen, R.D., Breuer, R.H., Egging, M., van Wijk, I.J., Oudejans, C.B. Clin. Cancer Res. (2002) [Pubmed]
  3. Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders: evidence for association of ASCL1 with Parkinson's disease. Ide, M., Yamada, K., Toyota, T., Iwayama, Y., Ishitsuka, Y., Minabe, Y., Nakamura, K., Hattori, N., Asada, T., Mizuno, Y., Mori, N., Yoshikawa, T. Hum. Genet. (2005) [Pubmed]
  4. HASH-1 and E2-2 are expressed in human neuroblastoma cells and form a functional complex. Persson, P., Jögi, A., Grynfeld, A., Påhlman, S., Axelson, H. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  5. Achaete-scute homolog-1 and Notch in lung neuroendocrine development and cancer. Ball, D.W. Cancer Lett. (2004) [Pubmed]
  6. Basic helix-loop-helix factors in cortical development. Ross, S.E., Greenberg, M.E., Stiles, C.D. Neuron (2003) [Pubmed]
  7. Evidence-based assessment of autism spectrum disorders in children and adolescents. Ozonoff, S., Goodlin-Jones, B.L., Solomon, M. Journal of clinical child and adolescent psychology : the official journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53. (2005) [Pubmed]
  8. Convergent and discriminant validity of measures of parenting efficacy and control. Lovejoy, M.C., Verda, M.R., Hays, C.E. Journal of clinical child psychology. (1997) [Pubmed]
  9. Origin of GABAergic neurons in the human neocortex. Letinic, K., Zoncu, R., Rakic, P. Nature (2002) [Pubmed]
  10. Molecular control of cell fate in the neural crest: the sympathoadrenal lineage. Anderson, D.J. Annu. Rev. Neurosci. (1993) [Pubmed]
  11. Divergent functions of the proneural genes Mash1 and Ngn2 in the specification of neuronal subtype identity. Parras, C.M., Schuurmans, C., Scardigli, R., Kim, J., Anderson, D.J., Guillemot, F. Genes Dev. (2002) [Pubmed]
  12. A molecular insight of Hes5-dependent inhibition of myelin gene expression: old partners and new players. Liu, A., Li, J., Marin-Husstege, M., Kageyama, R., Fan, Y., Gelinas, C., Casaccia-Bonnefil, P. EMBO J. (2006) [Pubmed]
  13. Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression. Chen, H., Thiagalingam, A., Chopra, H., Borges, M.W., Feder, J.N., Nelkin, B.D., Baylin, S.B., Ball, D.W. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  14. 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. Renault, B., Lieman, J., Ward, D., Krauter, K., Kucherlapati, R. Genomics (1995) [Pubmed]
  15. The Notch signaling cascade in neuroblastoma: role of the basic helix-loop-helix proteins HASH-1 and HES-1. Axelson, H. Cancer Lett. (2004) [Pubmed]
  16. Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse). 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. Hum. Mol. Genet. (2003) [Pubmed]
  17. Overexpression of the NOTCH1 Intracellular Domain Inhibits Cell Proliferation and Alters the Neuroendocrine Phenotype of Medullary Thyroid Cancer Cells. Kunnimalaiyaan, M., Vaccaro, A.M., Ndiaye, M.A., Chen, H. J. Biol. Chem. (2006) [Pubmed]
  18. Apoptosis-mediated medullary thyroid cancer growth suppression by the PI3K inhibitor LY294002. Kunnimalaiyaan, M., Ndiaye, M., Chen, H. Surgery (2006) [Pubmed]
  19. Differential actions of the proneural genes encoding Mash1 and neurogenins in Nurr1-induced dopamine neuron differentiation. Park, C.H., Kang, J.S., Kim, J.S., Chung, S., Koh, J.Y., Yoon, E.H., Jo, A.Y., Chang, M.Y., Koh, H.C., Hwang, S., Suh-Kim, H., Lee, Y.S., Kim, K.S., Lee, S.H. J. Cell. Sci. (2006) [Pubmed]
  20. Apoptotic speck protein-like, a highly homologous protein to apoptotic speck protein in the pyrin domain, is silenced by DNA methylation and induces apoptosis in human hepatocellular carcinoma. Kubo, T., Yamamoto, J., Shikauchi, Y., Niwa, Y., Matsubara, K., Yoshikawa, H. Cancer Res. (2004) [Pubmed]
  21. bHLH transcription factors and mammalian neuronal differentiation. Kageyama, R., Ishibashi, M., Takebayashi, K., Tomita, K. Int. J. Biochem. Cell Biol. (1997) [Pubmed]
  22. Complicated mechanisms of class II transactivator transcription deficiency in small cell lung cancer and neuroblastoma. Yazawa, T., Ito, T., Kamma, H., Suzuki, T., Okudela, K., Hayashi, H., Horiguchi, H., Ogata, T., Mitsui, H., Ikeda, M., Kitamura, H. Am. J. Pathol. (2002) [Pubmed]
  23. Interaction of Mash1 and Phox2b in sympathetic neuron development. Stanke, M., Stubbusch, J., Rohrer, H. Mol. Cell. Neurosci. (2004) [Pubmed]
  24. Large de novo deletion in chromosome 12 affecting the PAH, IGF1, ASCL1, and TRA1 genes. Mallolas, J., Vilaseca, M.A., Pavia, C., Lambruschini, N., Cambra, F.J., Campistol, J., Gómez, D., Carrió, A., Estivill, X., Milà, M. J. Mol. Med. (2001) [Pubmed]
  25. Patterns of gene expression in pituitary carcinomas and adenomas analyzed by high-density oligonucleotide arrays, reverse transcriptase-quantitative PCR, and protein expression. Ruebel, K.H., Leontovich, A.A., Jin, L., Stilling, G.A., Zhang, H., Qian, X., Nakamura, N., Scheithauer, B.W., Kovacs, K., Lloyd, R.V. Endocrine (2006) [Pubmed]
  26. Aberrant expression of human achaete-scute homologue gene 1 in the gastrointestinal neuroendocrine carcinomas. Shida, T., Furuya, M., Nikaido, T., Kishimoto, T., Koda, K., Oda, K., Nakatani, Y., Miyazaki, M., Ishikura, H. Clin. Cancer Res. (2005) [Pubmed]
  27. Tissue-specific expression of human achaete-scute homologue-1 in neuroendocrine tumors: transcriptional regulation by dual inhibitory regions. Chen, H., Biel, M.A., Borges, M.W., Thiagalingam, A., Nelkin, B.D., Baylin, S.B., Ball, D.W. Cell Growth Differ. (1997) [Pubmed]
  28. Acquisition of in vitro and in vivo functionality of Nurr1-induced dopamine neurons. Park, C.H., Kang, J.S., Shin, Y.H., Chang, M.Y., Chung, S., Koh, H.C., Zhu, M.H., Oh, S.B., Lee, Y.S., Panagiotakos, G., Tabar, V., Studer, L., Lee, S.H. FASEB J. (2006) [Pubmed]
  29. A BMP-mediated transcriptional cascade involving Cash1 and Tlx-3 specifies first-order relay sensory neurons in the developing hindbrain. Hornbruch, A., Ma, G., Ballermann, M.A., Tumova, K., Liu, D., Cairine Logan, C. Mech. Dev. (2005) [Pubmed]
  30. Identification of an achaete-scute homolog, Fash1, from Fugu rubripes. Verma-Kurvari, S., Johnson, J.E. Gene (1997) [Pubmed]
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