NOTCH1 gene transcription

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Reaction [omitted]
Homo sapiens
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NOTCH1 was cloned as a chromosome 9 gene involved in translocation t(7;9)(q34;q34.3) in several T-cell acute lymphoblastic leukemia (T-ALL) patients. The gene was found to be highly homologous to the Drosophila gene Notch and was initially named TAN-1 (translocation-associated Notch homolog). Transcripts of NOTCH1 were detected in many fetal and adult human and mouse tissues, with the highest abundance in lymphoid tissues. The translocation t(7;9)(q34;q34.3) found in a small fraction of T-ALL patients puts NOTCH1 transcription under the control of the T-cell receptor-beta (TCRB) locus, which results in expression of truncated peptides that lack the extracellular ligand binding domain and are constitutively active (reviewed by Grabher et al. 2006). Activating NOTCH1 point mutations, mainly affecting the extracellular heterodimerization domain and/or the C-terminal PEST domain, are found in more than 50% of human T-ALLs (Weng et al. 2004).

Studies of mouse Rbpj knockout embryos and zebrafish Mib (mindbomb) mutants indicate that the NOTCH1 coactivator complex positively regulates NOTCH1 transcription. The RBPJ-binding site(s) that the NOTCH1 coactivator complex normally binds have not been found in the NOTCH1 promoter, however, so this effect may be indirect and its mechanism is unknown (Del Monte et al. 2007).

CCND1 (cyclin D1) forms a complex with CREBBP and binds to the NOTCH1 promoter, stimulating NOTCH1 transcription. The involvement of CCND1 in transcriptional regulation of NOTCH1 was established in mouse retinas and the rat retinal precursor cell line R28 (Bienvenu et al. 2010).

E2F1 and E2F3 are able to bind to the NOTCH1 promoter and activate NOTCH1 transcription (Viatour et al. 2011).

NOTCH1 promoter possesses two putative p53-binding sites. Chromatin immunoprecipitation (ChIP) assays of human primary keratinocytes showed binding of endogenous p53 protein to both sites. Experiments in which p53 was downregulated or overexpressed implicate p53 as a positive regulator of NOTCH1 expression in primary human keratinocytes. It is likely that p53-mediated regulation of NOTCH1 expression involves interplay with other cell-type specific determinants of gene expression (Lefort et al. 2007). In lymphoid cells, NOTCH1 expression may be negatively regulated by p53 (Laws and Osborne 2004). Other proteins implicated in the negative regulation of NOTCH1 transcription are KLF9 (Ying et al. 2011), JARID2 (Mysliwiec et al. 2011, Mysliwiec et al. 2012), KLF4 and SP3 (Lambertini et al. 2010), and p63 (Yugawa et al. 2010).

Literature References
PubMed ID Title Journal Year
15472075 Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia

Lee, W, Blacklow, SC, Silverman, LB, Look, AT, Sanchez-Irizarry, C, Aster, JC, Ferrando, AA, Weng, AP, Morris JP, 4th

Science 2004
16612405 Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia

von Boehmer, H, Look, AT, Grabher, C

Nat Rev Cancer 2006
20442293 DeltaNp63alpha repression of the Notch1 gene supports the proliferative capacity of normal human keratinocytes and cervical cancer cells

Egawa, N, Yoshimatsu, Y, Kiyono, T, Fujita, M, Haga, K, Narisawa-Saito, M, Yugawa, T, Ohno, S

Cancer Res. 2010
21875955 Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway

Saddic, LA, Zmoos, AF, Sylvester, KG, Ehmer, U, Sage, J, Dorrell, C, Lin, C, Viatour, P, Grompe, M, Thorgeirsson, SS, Mazur, PK, Schaffer, BE, Andersen, JB, Vogel, H, Ostermeier, A

J Exp Med 2011
17685488 Monitoring Notch1 activity in development: evidence for a feedback regulatory loop

Bolós, V, Grego-Bessa, J, González-Rajal, A, De La Pompa, JL, Del Monte, G

Dev. Dyn. 2007
20442780 Differential control of Notch1 gene transcription by Klf4 and Sp3 transcription factors in normal versus cancer-derived keratinocytes

Pantano, S, Dotto, GP, Lambertini, C

PLoS ONE 2010
21280156 Krüppel-like family of transcription factor 9, a differentiation-associated transcription factor, suppresses Notch1 signaling and inhibits glioblastoma-initiating stem cells

Ying, M, Guerrero-Cazares, H, Laterra, J, Li, Y, Sang, Y, Vescovi, AL, Quinones-Hinojosa, A, Xia, S, Eberhart, CG

Stem Cells 2011
21402699 Endothelial Jarid2/Jumonji is required for normal cardiac development and proper Notch1 expression

Lee, Y, Bresnick, EH, Mysliwiec, MR

J. Biol. Chem. 2011
22110129 Jarid2 (Jumonji, AT rich interactive domain 2) regulates NOTCH1 expression via histone modification in the developing heart

Ansari, AZ, Hung, H, Tietjen, J, Lee, Y, Carlson, CD, Mysliwiec, MR

J. Biol. Chem. 2012
17344417 Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases

Neel, V, Hohl, D, Garlick, J, Lefort, K, Mandinova, A, Kolfschoten, I, Ostano, P, Chiorino, G, Raffoul, W, Calpini, V, Kolev, V, Dotto, GP, Lieb, J, Devgan, V

Genes Dev 2007
20090754 Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen

Gygi, SP, Liu, XS, Geng, Y, Mizeracka, K, Jirawatnotai, S, Meyer, CA, Elias, JE, Cole, MF, Sicinski, P, Bienvenu, F, Young, RA, Frampton, GM, Odajima, J, Cepko, CL, Zagozdzon, A, Jecrois, M, Odom, DT, Marson, A

Nature 2010
14991602 p53 regulates thymic Notch1 activation

Osborne, BA, Laws, AM

Eur J Immunol 2004
1831692 TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms

Smith, SD, Sklar, J, Ellisen, LW, Bird, J, West, DC, Soreng, AL, Reynolds, TC

Cell 1991
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