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Gene Review

HES1  -  hes family bHLH transcription factor 1

Homo sapiens

Synonyms: BHLHB39, Class B basic helix-loop-helix protein 39, FLJ20408, HES-1, HHL, ...
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Disease relevance of HES1


Psychiatry related information on HES1

  • However, the Id proteins did complex with HES-1, and increased levels of Id2 reduced the DNA binding activity of HES-1 [6].

High impact information on HES1

  • Here we show that Hes1 is expressed in the extrahepatic biliary epithelium throughout development and that Hes1-deficient mice have gallbladder agenesis and severe hypoplasia of extrahepatic bile ducts [7].
  • Thus, biliary epithelium has the potential for pancreatic differentiation and Hes1 determines biliary organogenesis by preventing the pancreatic differentiation program, probably by directly repressing transcription of Neurog3 [7].
  • Conversion of biliary system to pancreatic tissue in Hes1-deficient mice [7].
  • Mammalian homologues of E(Spl), such as the mouse Hairy enhancer of split (HES-1), have been isolated [8].
  • Conditional deletion of Rbp-J, which encodes the major mediator of the Notch pathway, leads to premature differentiation of progenitor cells, a phenotype recapitulated by loss of the basic helix-loop-helix (bHLH) factor Hes1, as well as a conversion of the late (Pit1) lineage into the early (corticotrope) lineage [9].

Chemical compound and disease context of HES1


Biological context of HES1

  • Furthermore, we demonstrate that the suppression of HES1 expression initiates differentiation of neural stem cells into neurons, the majority of which develop the GABAergic phenotype [15].
  • Notch activation, assayed by inhibition of differentiation in C2 myoblasts and by HES1 transactivation in U20S cells, occurred when either Delta-1(ext-myc) or Delta-1(ext-IgG) were first immobilized on the plastic surface [16].
  • The Notch1 dimer formation increased in response to ligand presentation and HES1 promoter was stimulated, implying that receptor homodimerization is an important initial step in Notch signal transduction [17].
  • Thus, HES1 regulates brain and eye morphogenesis by inhibiting premature neuronal differentiation, and the down-regulation of HES1 expression at the right time is required for normal development of the nervous system [18].
  • The NGF-induced transcription of the c-jun, HES1 and Bc12 genes is, in contrast, cell type-specific, indicating that NGF can trigger different gene expression programs dependent on the signaling pathways present in a particular cell type [19].

Anatomical context of HES1

  • These findings underscore the importance of the HLH network, and HES1 in particular, in guiding the phenotypic development of neural stem cells [15].
  • Expression of HES1 increased significantly during chondrogenesis in chondrocytes while expression in MSCs was maintained at a low level [20].
  • RESULTS: The results of this study demonstrated, for the first time, that both Jagged1 and Delta1 ligands and the downstream effector gene HES1 are expressed in the HepG2 actively proliferating cell line [21].
  • We demonstrate that HES1, a principal member of this family, is normally expressed in the nuclei of human biliary epithelial cells up to 16 weeks of gestation, but not in later gestation or in the neonatal period [4].
  • Ectopic expression of Hairy/Enhancer of Split 1 (HES1) consistently reproduced the inhibitory effect of N(IC) on endothelial cell proliferation [22].

Associations of HES1 with chemical compounds


Physical interactions of HES1

  • Our studies also show that HES-1 can antagonize the binding of Cbfa1 to mammalian transcriptional corepressors of the Groucho family [27].

Enzymatic interactions of HES1

  • One important negative regulator of MASH-1 expression is the bHLH factor hairy and Enhancer of split homolog-1 (HES-1), which in turn is under positive control of the Notch signaling cascade [28].
  • Purification of Hes-1 identified the Groucho/transducin-like enhancer of split family of corepressors as the only significant Hes-1 interacting proteins in vivo [29].

Regulatory relationships of HES1


Other interactions of HES1

  • This correlated with the initiation of signaling downstream of Notch, as evidenced by increased levels of HES-1 transcripts in co-cultivated T cells and of CD23 transcripts in co-cultivated B cells [32].
  • On N box-containing promoters, HES6 cooperated with HES1 to achieve maximal repression [33].
  • Previously, we identified an intronic repressor element in the GAA gene and demonstrated that Hes-1, a basic helix-loop-helix factor, binds to a C class E box within the element and functions as a transcriptional repressor in HepG2 cells [34].
  • Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif [35].
  • Here we demonstrate that the human Sir2 homologue, SIRT1, also physically associates with the human bHLH repressor proteins, hHES1 and hHEY2, both in vitro and in vivo [36].

Analytical, diagnostic and therapeutic context of HES1


  1. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Sriuranpong, V., Borges, M.W., Ravi, R.K., Arnold, D.R., Nelkin, B.D., Baylin, S.B., Ball, D.W. Cancer Res. (2001) [Pubmed]
  2. The Notch pathway in ovarian carcinomas and adenomas. Hopfer, O., Zwahlen, D., Fey, M.F., Aebi, S. Br. J. Cancer (2005) [Pubmed]
  3. Transcriptional regulation of human MAP2 gene in melanoma: role of neuronal bHLH factors and Notch1 signaling. Bhat, K.M., Maddodi, N., Shashikant, C., Setaluri, V. Nucleic Acids Res. (2006) [Pubmed]
  4. Extrahepatic biliary atresia demonstrates abnormal persistence of HES1 protein in neonatal biliary epithelium: an immunohistochemical study. Rakheja, D., Maitra, A., Kapur, P., Weinberg, A.G. Pediatr. Dev. Pathol. (2006) [Pubmed]
  5. Rbm15 modulates notch-induced transcriptional activation and affects myeloid differentiation. Ma, X., Renda, M.J., Wang, L., Cheng, E.C., Niu, C., Morris, S.W., Chi, A.S., Krause, D.S. Mol. Cell. Biol. (2007) [Pubmed]
  6. Modulation of basic helix-loop-helix transcription complex formation by Id proteins during neuronal differentiation. Jögi, A., Persson, P., Grynfeld, A., Påhlman, S., Axelson, H. J. Biol. Chem. (2002) [Pubmed]
  7. Conversion of biliary system to pancreatic tissue in Hes1-deficient mice. Sumazaki, R., Shiojiri, N., Isoyama, S., Masu, M., Keino-Masu, K., Osawa, M., Nakauchi, H., Kageyama, R., Matsui, A. Nat. Genet. (2004) [Pubmed]
  8. Signalling downstream of activated mammalian Notch. Jarriault, S., Brou, C., Logeat, F., Schroeter, E.H., Kopan, R., Israel, A. Nature (1995) [Pubmed]
  9. Sustained Notch signaling in progenitors is required for sequential emergence of distinct cell lineages during organogenesis. Zhu, X., Zhang, J., Tollkuhn, J., Ohsawa, R., Bresnick, E.H., Guillemot, F., Kageyama, R., Rosenfeld, M.G. Genes Dev. (2006) [Pubmed]
  10. The anti-estrogenic effect of all-trans-retinoic acid on the breast cancer cell line MCF-7 is dependent on HES-1 expression. Muller, P., Kietz, S., Gustafsson, J.A., Strom, A. J. Biol. Chem. (2002) [Pubmed]
  11. The Hairy and Enhancer of Split homologue-1 (HES-1) mediates the proliferative effect of 17beta-estradiol on breast cancer cell lines. Ström, A., Arai, N., Leers, J., Gustafsson, J.A. Oncogene (2000) [Pubmed]
  12. An intermediate in the assembly of a pore-forming protein trapped with a genetically-engineered switch. Walker, B., Braha, O., Cheley, S., Bayley, H. Chem. Biol. (1995) [Pubmed]
  13. Farnesoid X receptor represses hepatic lipase gene expression. Sirvent, A., Verhoeven, A.J., Jansen, H., Kosykh, V., Darteil, R.J., Hum, D.W., Fruchart, J.C., Staels, B. J. Lipid Res. (2004) [Pubmed]
  14. A novel cis-acting element regulates HES-1 gene expression in P19 embryonal carcinoma cells treated with retinoic acid. Wakabayashi, N., Kageyama, R., Habu, T., Doi, T., Morita, T., Nozaki, M., Yamamoto, M., Nishimune, Y. J. Biochem. (2000) [Pubmed]
  15. Blocking HES1 expression initiates GABAergic differentiation and induces the expression of p21(CIP1/WAF1) in human neural stem cells. Kabos, P., Kabosova, A., Neuman, T. J. Biol. Chem. (2002) [Pubmed]
  16. Immobilization of Notch ligand, Delta-1, is required for induction of notch signaling. Varnum-Finney, B., Wu, L., Yu, M., Brashem-Stein, C., Staats, S., Flowers, D., Griffin, J.D., Bernstein, I.D. J. Cell. Sci. (2000) [Pubmed]
  17. Distinct roles of EGF repeats for the Notch signaling system. Sakamoto, K., Chao, W.S., Katsube, K., Yamaguchi, A. Exp. Cell Res. (2005) [Pubmed]
  18. bHLH transcription factors and mammalian neuronal differentiation. Kageyama, R., Ishibashi, M., Takebayashi, K., Tomita, K. Int. J. Biochem. Cell Biol. (1997) [Pubmed]
  19. Nerve growth factor- and epidermal growth factor-regulated gene transcription in PC12 pheochromocytoma and INS-1 insulinoma cells. Groot, M., Boxer, L.M., Thiel, G. Eur. J. Cell Biol. (2000) [Pubmed]
  20. Differentiation of human mesenchymal stem cells and articular chondrocytes: Analysis of chondrogenic potential and expression pattern of differentiation-related transcription factors. Karlsson, C., Brantsing, C., Svensson, T., Brisby, H., Asp, J., Tallheden, T., Lindahl, A. J. Orthop. Res. (2007) [Pubmed]
  21. Notch3 intracellular domain accumulates in HepG2 cell line. Giovannini, C., Lacchini, M., Gramantieri, L., Chieco, P., Bolondi, L. Anticancer Res. (2006) [Pubmed]
  22. Inhibition of endothelial cell proliferation by Notch1 signaling is mediated by repressing MAPK and PI3K/Akt pathways and requires MAML1. Liu, Z.J., Xiao, M., Balint, K., Soma, A., Pinnix, C.C., Capobianco, A.J., Velazquez, O.C., Herlyn, M. FASEB J. (2006) [Pubmed]
  23. HES-1, a novel target gene for the aryl hydrocarbon receptor. Thomsen, J.S., Kietz, S., Ström, A., Gustafsson, J.A. Mol. Pharmacol. (2004) [Pubmed]
  24. Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Wang, Z., Zhang, Y., Banerjee, S., Li, Y., Sarkar, F.H. Cancer (2006) [Pubmed]
  25. Proteomics of bovine mitochondrial RNA-binding proteins: HES1/KNP-I is a new mitochondrial resident protein. Ponamarev, M.V., She, Y.M., Zhang, L., Robinson, B.H. J. Proteome Res. (2005) [Pubmed]
  26. Phosphorylation of serine 239 of Groucho/TLE1 by protein kinase CK2 is important for inhibition of neuronal differentiation. Nuthall, H.N., Joachim, K., Stifani, S. Mol. Cell. Biol. (2004) [Pubmed]
  27. The mammalian basic helix loop helix protein HES-1 binds to and modulates the transactivating function of the runt-related factor Cbfa1. McLarren, K.W., Lo, R., Grbavec, D., Thirunavukkarasu, K., Karsenty, G., Stifani, S. J. Biol. Chem. (2000) [Pubmed]
  28. 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]
  29. Functional analysis of Hes-1 in preadipocytes. Ross, D.A., Hannenhalli, S., Tobias, J.W., Cooch, N., Shiekhattar, R., Kadesch, T. Mol. Endocrinol. (2006) [Pubmed]
  30. The soluble Notch ligand, Jagged-1, inhibits proliferation of CD34+ macrophage progenitors. Masuya, M., Katayama, N., Hoshino, N., Nishikawa, H., Sakano, S., Araki, H., Mitani, H., Suzuki, H., Miyashita, H., Kobayashi, K., Nishii, K., Minami, N., Shiku, H. Int. J. Hematol. (2002) [Pubmed]
  31. Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3. Blokzijl, A., Dahlqvist, C., Reissmann, E., Falk, A., Moliner, A., Lendahl, U., Ibáñez, C.F. J. Cell Biol. (2003) [Pubmed]
  32. Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors. Bash, J., Zong, W.X., Banga, S., Rivera, A., Ballard, D.W., Ron, Y., Gélinas, C. EMBO J. (1999) [Pubmed]
  33. HES6 acts as a transcriptional repressor in myoblasts and can induce the myogenic differentiation program. Gao, X., Chandra, T., Gratton, M.O., Quélo, I., Prud'homme, J., Stifani, S., St-Arnaud, R. J. Cell Biol. (2001) [Pubmed]
  34. The human acid alpha-glucosidase gene is a novel target of the Notch-1/Hes-1 signaling pathway. Yan, B., Raben, N., Plotz, P. J. Biol. Chem. (2002) [Pubmed]
  35. Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif. Grbavec, D., Stifani, S. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  36. Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression. Takata, T., Ishikawa, F. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  37. Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-beta. Ostroukhova, M., Qi, Z., Oriss, T.B., Dixon-McCarthy, B., Ray, P., Ray, A. J. Clin. Invest. (2006) [Pubmed]
  38. NOTCH1 mutations are rare in acute myeloid leukemia. Fu, L., Kogoshi, H., Nara, N., Tohda, S. Leuk. Lymphoma (2006) [Pubmed]
  39. The notch signaling system is present in the postnatal pituitary: marked expression and regulatory activity in the newly discovered side population. Chen, J., Crabbe, A., Van Duppen, V., Vankelecom, H. Mol. Endocrinol. (2006) [Pubmed]
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