hes1-protein--human and Neoplasms

Apoptosis is a normally biological phenomenon in various organisms, involving complexly molecular mechanisms with a series of signaling processes. Notch signaling is found evolutionarily conserved in many species, playing a critical role in embryonic development, normal tissue homeostasis, angiogenesis and immunoregulation. The focus of this review is on currently novel advances about roles of CSL-dependent and independent Notch signaling pathways in cell apoptosis. The CSL can bind Notch intracellular domain (NIC) to act as a switch in mediating transcriptional activation or inactivation of the Notch signaling pathway downstream genes in the nucleus. It shows that CSL-dependent signaling regulates the cell apoptosis through Hes-1-PTEN-AKT-mTOR signaling, but rather the CSL-independent signaling mediates the cell apoptosis possibly via NIC-mTORC2-AKT-mTOR signaling, providing a new insight into apoptotic mechanisms.

Topics: Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Carcinogenesis; Cell Proliferation; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Immunoglobulin J Recombination Signal Sequence-Binding Protein; Neoplasms; Neovascularization, Pathologic; Protein Isoforms; Protein Structure, Tertiary; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Receptor, Notch1; Signal Transduction; TOR Serine-Threonine Kinases; Transcription Factor HES-1

Hairy and enhancer of split homolog-1 (HES1) is a part of an extensive family of basic helix-loop-helix (bHLH) proteins and plays a crucial role in the control and regulation of cell cycle, proliferation, cell differentiation, survival and apoptosis in neuronal, endocrine, T-lymphocyte progenitors as well as various cancers. HES1 is a transcription factor which is regulated by the NOTCH, Hedgehog and Wnt signalling pathways. Aberrant expression of these pathways is a common feature of cancerous cells. There appears to be a fine and complicated crosstalk at the molecular level between the various signalling pathways and HES1, which contributes to its effects on the immune response and cancers such as leukaemia. Several mechanisms have been proposed, including an enhanced invasiveness and metastasis by inducing epithelial mesenchymal transition (EMT), in addition to its strict requirement for tumour cell survival. In this review, we summarize the current biology and molecular mechanisms as well as its use as a clinical target in cancer therapeutics.

Topics: Animals; Cytokines; Humans; Neoplasms; Transcription Factor HES-1

Quiescent and tumor cells share the ability to evade irreversible cell fates. Recent studies have shown that the transcriptional regulator Hairy and Enhancer of Split 1 (HES1) protects quiescent fibroblasts from differentiation or senescence. HES1 is highly expressed in rhabdomyosarcomas, and the inhibition of HES1 restores differentiation in these cells. Pathways that lead to elevated HES1 levels, such as the Notch and Hedgehog pathways, are frequently upregulated in tumors. Compounds that inhibit these pathways induce differentiation and apoptosis in cancer cells and several are in clinical trials. HES1 might repress gene expression in part by recruiting histone deacetylases (HDACs). HDACs inhibit differentiation, whereas histone deacetylase inhibitors (HDACis) induce differentiation or apoptosis in tumors and are also showing promise as therapeutics. Small molecules that directly target HES1 itself were recently identified. Here, we discuss the importance of HES1 function in quiescent and tumor cells. Elucidating the pathways that control quiescence could provide valuable information not only for treating cancer but also other diseases.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Cycle; Cell Differentiation; Gene Expression Regulation, Neoplastic; Histone Deacetylases; Homeodomain Proteins; Humans; Neoplasms; Protein Binding; Transcription Factor HES-1

Notch signaling plays critical roles in cancer progression, motivating efforts to identify inhibitors of this pathway. Perron

Topics: Antineoplastic Agents; High-Throughput Screening Assays; Humans; Neoplasms; Protein Multimerization; Receptors, Notch; Small Molecule Libraries; Transcription Factor HES-1

Notch3 receptor is expressed in a variety of cancers and the excised active intracellular domain (N3ICD) initiates its signaling cascade. N-acetylcysteine (NAC) as an antioxidant has been implicated in cancer prevention and therapy. In this study, we demonstrated a negative regulation of Notch3 by NAC in cancer cells. HeLa cells treated with NAC exhibited a time- and concentration-dependent decrease in Notch3 levels and its downstream effectors Hes1 and HRT1 in a manner independent of f-secretase or glutathione. In contrast, NAC did not affect protein levels of Notch1, the full length Notch3 precursor, or ectopically expressed N3ICD. Although SOD, catalase and NAC suppressed reactive oxygen species in HeLa cells, the first two antioxidants did not impact on Notch3 levels. While the mRNA expression of Notch3 was not altered by NAC, functional inhibition of lysosome, but not proteasome, blocked the NAC-dependent reduction of Notch3 levels. Furthermore, results from Notch3 silencing and N3ICD overexpression demonstrated that NAC prevented malignant phenotypes through down-regulation of Notch3 protein in multiple cancer cells. In summary, NAC reduces Notch3 levels through lysosome-dependent protein degradation, thereby negatively regulates Notch3 malignant signaling in cancer cells. These results implicate a novel NAC treatment in sensitizing Notch3-expressing tumors.

Topics: Acetylcysteine; Amyloid Precursor Protein Secretases; Basic Helix-Loop-Helix Transcription Factors; Catalase; Cell Cycle Proteins; Down-Regulation; Gene Knockdown Techniques; Glutathione; HeLa Cells; Humans; Lysosomes; MCF-7 Cells; Neoplasms; Proteasome Endopeptidase Complex; Protein Domains; Reactive Oxygen Species; Receptor, Notch1; Receptor, Notch3; RNA Interference; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Superoxide Dismutase; Transcription Factor HES-1

Tuberous sclerosis complex (TSC) is a dominantly inherited disease that is characterized by the growth of multiple benign tumors that are often difficult to treat. TSC is caused by mutations that inactivate the TSC1 or TSC2 genes, which normally function to inhibit activation of mammalian target of rapamycin signaling. In this issue of the JCI, two studies reported by Karbowniczek et al. and Ma et al. link TSC inactivation with activated Notch signaling (see the related articles beginning on pages 93 and 103, respectively). Using a variety of approaches, both studies show that inactivation of TSC leads to Notch1 activation. Furthermore, studies in tumor cells suggest that inhibiting Notch slows growth of the tumor cells. Although much remains to be learned about the precise mechanisms by which TSC loss leads to Notch activation, the newly identified link of TSC to Notch provides the rationale for testing Notch inhibitors in TSC-associated tumors.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Homeodomain Proteins; Humans; Monomeric GTP-Binding Proteins; Neoplasms; Neuropeptides; Protein Kinases; Ras Homolog Enriched in Brain Protein; Receptors, Notch; Signal Transduction; TOR Serine-Threonine Kinases; Transcription Factor HES-1; Transcription Factors; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Mutations in one of the 13 Fanconi anemia (FA) genes cause a progressive bone marrow failure disorder associated with developmental abnormalities and a predisposition to cancer. Although FA has been defined as a DNA repair disease based on the hypersensitivity of patient cells to DNA cross-linking agents, FA patients develop various developmental defects such as skeletal abnormalities, microphthalmia, and endocrine abnormalities that may be linked to transcriptional defects. Recently, we reported that the FA core complex interacts with the transcriptional repressor Hairy Enhancer of Split 1 (HES1) suggesting that the core complex plays a role in transcription. Here we show that the FA core complex contributes to transcriptional regulation of HES1-responsive genes, including HES1 and the cyclin-dependent kinase inhibitor p21(cip1/waf1). Chromatin immunoprecipitation studies show that the FA core complex interacts with the HES1 promoter but not the p21(cip1/waf1) promoter. Furthermore, we show that the FA core complex interferes with HES1 binding to the co-repressor transducin-like-Enhancer of Split, suggesting that the core complex affects transcription both directly and indirectly. Taken together these data suggest a novel function of the FA core complex in transcriptional regulation.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Chlorocebus aethiops; COS Cells; Cross-Linking Reagents; Cyclin-Dependent Kinase Inhibitor p21; DNA Repair; Fanconi Anemia; Fanconi Anemia Complementation Group Proteins; Genetic Predisposition to Disease; Homeodomain Proteins; Humans; Multiprotein Complexes; Mutation; Neoplasms; Signal Transduction; Transcription Factor HES-1; Transcription, Genetic