Disease relevance of HES1

• Notch proteins, but not HES1 or control adenoviruses, caused a profound growth arrest, associated with a G1 cell cycle block [1].
• HES1 protein was strongly expressed in 18/19 ovarian cancers and borderline tumours but not in adenomas [2].
• Melanoma cells express both NeuroD and HES1 [3].
• Extrahepatic biliary atresia demonstrates abnormal persistence of HES1 protein in neonatal biliary epithelium: an immunohistochemical study [4].
• Rbm15 inhibits Notch-induced HES1 transcription in nonhematopoietic cells but stimulates this activity in hematopoietic cell lines, including 32DWT18 and human erythroleukemia cells [5].

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

• The anti-estrogenic effect of all-trans-retinoic acid on the breast cancer cell line MCF-7 is dependent on HES-1 expression [10].
• We show that the HES-1 protein level in the breast cancer cell lines T47D and MCF-7 is down regulated by 17beta-estradiol treatment [11].
• The alpha-hemolysin (alpha HL) protein, an exotoxin secreted by Staphylococcus aureus that forms heptameric pores in lipid bilayers, is a useful model for studying membrane protein assembly [12].
• The natural FXR ligand, chenodeoxycholic acid (CDCA), downregulates HL gene expression in a dose- and time-dependent manner in human hepatoma HepG2 cells [13].
• A novel cis-acting element regulates HES-1 gene expression in P19 embryonal carcinoma cells treated with retinoic acid [14].

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

• Also, we have previously shown that HES-1 is down-regulated by the estrogen receptor ligand 17beta-estradiol (E2) [23].
• Up-regulation of HES-1 expression is correlated with suppression of cell proliferation, and the E2-mediated down-regulation of HES-1 therefore increases cell proliferation [23].
• Notch-1, Hes-1, and Bcl-XL expression levels concomitantly were down-regulated by curcumin treatment [24].
• HES1/KNP-I from the polyA-binding fraction of mitochondrial Triton extract showed exclusive mitochondrial localization when expressed in GFP-tagged form [25].
• Mutation of serine 239 into alanine decreases Hes1-induced hyperphosphorylation of Gro/TLE1 and also reduces its nuclear association and transcription repression activity [26].

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

• Conversely, null mutation of HES1 up-regulates Mash1 expression, accelerates neuronal differentiation, and causes severe defects of the brain and eyes [18].
• Here we show that the HLH transcription factor HES1 regulates the proliferation of human neural stem cells and that blocking its expression stimulates the expression of cyclin-dependent kinase inhibitor p21(CIP1/WAF1) [15].
• The direct action of hJagged-1 was confirmed by the enhanced expression of the HES-1 (hairy enhancer of the split-1) gene [30].
• Activation of TGF-beta signaling up-regulated Hes-1 expression in vitro and in vivo [31].
• We conclude that Notch most likely blocks adipogenesis through the induction of Hes-1 homodimers, which repress transcription of key target genes [29].

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

• Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-beta [37].
• Further studies should be performed to evaluate the role of HES1 immunohistochemistry as a diagnostic tool in extrahepatic biliary atresia [4].
• Chromatin immunoprecipitation showed that in metastatic melanoma cells N-box region of the MAP2 promoter is occupied by endogenous HES1 [3].
• The sample with the mutation expressed the intracellular Notch1 fragment by immunoblotting and HES1 mRNA by reverse transcription-polymerase chain reaction [38].
• Using RT-PCR, we detected in the anterior pituitary of adult mouse the expression of all four vertebrate Notch receptors, as well as of Hes1, 5, and 6, key downstream targets and effectors of Notch [39].

References