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Gene Review

NOTCH1  -  notch 1

Homo sapiens

Synonyms: AOS5, AOVD1, Neurogenic locus notch homolog protein 1, Notch 1, TAN1, ...
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Disease relevance of NOTCH1

  • Recent work has shown that human T-ALL is frequently associated with C-terminal NOTCH1 truncations, which uniformly remove sequences lying between residues 2524 and 2556 [1].
  • High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival [2].
  • NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in multifactorial leukemogenesis [3].
  • Here, we report a new human T-cell lymphoma line CUTLL1, which expresses high levels of activated NOTCH1 and is extremely sensitive to gamma-secretase inhibitors treatment [4].
  • Activating mutations in NOTCH1 are present in over 50% of human T-cell lymphoblastic leukemia (T-ALL) samples and inhibition of NOTCH1 signaling with gamma-secretase inhibitors (GSI) has emerged as a potential therapeutic strategy for the treatment of this disease [4].
  • The ability of this model to detect a strong interaction between NOTCH1 and bcl2 suggests that genetic modifier screens have a high likelihood of revealing other genes that can cooperate with NOTCH1 to induce T-ALL [5].
  • Cells inactivated for hCdc4 and T-ALL cells containing hCDC4 mutations exhibited an increased Notch1 protein half-life, consistent with the proposed role of hCdc4 in ubiquitin-dependent proteolysis of Notch1 [6].
  • We conclude that NOTCH1 can be an early or initiating event in T-ALL arising prenatally, to be complemented by a postnatal SIL-TAL1 fusion [7].
  • Notch1 facilitated melanoma development in a xenograft model by maintaining cell proliferation and by protecting cells from stress-induced cell death [8].

Psychiatry related information on NOTCH1

  • Furthermore, the fact that inhibitors first target gamma-secretase in the plasma membrane for Notch processing, and not for APP, will have important implications for drug development to treat Alzheimer's disease and cancer [9].
  • Against a background of consistent gene expression, several regulatory genes show marked differences between fetal and adult expression profiles, including those encoding two basic helix-loop-helix antagonist Id factors, the Ets family factor SpiB and the Notch target gene Deltex1 [10].
  • Transient administration of Notch ligands to the brain of adult rats increases the numbers of newly generated precursor cells and improves motor skills after ischaemic injury [11].
  • Human Genetics. Notch, stroke and dementia [12].
  • Notch-1 immunoexpression is increased in Alzheimer's and Pick's disease [13].

High impact information on NOTCH1

  • Commitment to the T cell lineage and subsequent stages of early thymopoiesis is critically regulated by Notch [14].
  • Recent data indicate that Notch can also direct the differentiation and activity of peripheral T and B cells [14].
  • The transmembrane receptor Notch participates in diverse cell fate decisions throughout embryonic development [15].
  • Notch receptors and their ligands are expressed in the mammalian thymus, raising the possibility that Notch could regulate T cell fate decisions [15].
  • Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes [16].

Chemical compound and disease context of NOTCH1


Biological context of NOTCH1

  • In human acute lymphoblastic T-cell leukemia, a chromosomal translocation damages the NOTCH1 gene [22].
  • These data are most consistent with NOTCH1 oncogenesis and transcriptional activation being independent of association with RBP-Jkappa at promoter sites [23].
  • Oncogenic forms of NOTCH1 lacking either the primary binding site for RBP-Jkappa or nuclear localization sequences retain the ability to associate with RBP-Jkappa and activate transcription [23].
  • Unlike full-sized NOTCH1, two such truncated forms of the protein either lacking a major portion of the extracellular domain (DeltaE) or consisting only of the intracellular domain (ICN) were found to activate transcription in cultured cells, presumably through RBP-Jkappa response elements within DNA [23].
  • In contrast with most human T-ALL cell lines with activating mutations in NOTCH1, CUTLL1 cells showed a robust cellular phenotype upon GSI treatment characterized by G1 cell cycle arrest and increased apoptosis [4].

Anatomical context of NOTCH1

  • NOTCH1 is a large type I transmembrane receptor that regulates normal T-cell development via a signaling pathway that relies on regulated proteolysis [1].
  • These studies show that continued growth and survival of NOTCH1-transformed lymphoid cell lines require nuclear access and transcriptional coactivator recruitment by NOTCH1 and identify at least two steps in the Notch signaling pathway as potential targets for chemotherapeutic intervention [24].
  • Consistent with these in vitro studies, mutation of the WSSSSP sequence converts nonleukemogenic weak gain-of-function NOTCH1 alleles into alleles that cause aggressive T-ALLs in a murine bone marrow transplant model [1].
  • CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gamma-secretase inhibitors [4].
  • Mutations in NOTCH1 cause aortic valve disease [25].

Associations of NOTCH1 with chemical compounds

  • The activating mutations cause soluble NOTCH1 heterodimers to dissociate more readily, either under native conditions (n = 3) or in the presence of urea (n = 11) [26].
  • However, activation of only Notch-1, but not Notch-2, resulted in protection of tumor cells from melphalan- and mitoxantrone-induced apoptosis [27].
  • Using a cell line deficient for the T cell-specific, Src family protein, the tyrosine kinase p56(lck) and by reconstitution approaches we demonstrate that p56(lck) is required for the Notch-1-mediated activation of Akt/PKB function [28].
  • NOV associates with the epidermal growth factor-like repeats of Notch1 by the CT (C-terminal cysteine knot) domain [29].
  • Aspartate mutations in presenilin and gamma-secretase inhibitors both impair notch1 proteolysis and nuclear translocation with relative preservation of notch1 signaling [30].

Physical interactions of NOTCH1

  • Furthermore we found that full-length expressed WWP1 could interact in vitro with the cytoplasmic domain of human Notch1 [31].
  • JAG1 then binds to the Notch receptor on adjacent stem cells to induce Notch receptor proteolyses for the release of Notch intracellular domain (NICD) [32].
  • The cleaved intracellular region (RAMIC) of Notch is translocated into the nucleus and interacts with a DNA-binding protein RBP-J to activate transcription of genes that regulate cell differentiation [33].
  • Rapid Notch1 nuclear translocation after ligand binding depends on presenilin-associated gamma-secretase activity [34].
  • Consistent with these results, we found that the down-regulation of Notch-1 reduced NF-kappaB DNA-binding activity and VEGF expression [35].

Enzymatic interactions of NOTCH1

  • Activation of Notch1 signaling in the RA synovium was identified using a specific antibody to the cleaved form of Notch1 [36].
  • The NOTCH1 receptor is cleaved within its extracellular domain by furin during its maturation, yielding two subunits that are held together noncovalently by a juxtamembrane heterodimerization (HD) domain [26].
  • Moreover, non-denaturing isolation of the intact enzyme complex revealed that cell surface gamma-secretase can specifically generate amyloid beta-protein from an APP substrate and similarly cleave a Notch substrate [37].
  • After ligand binding, Notch is cleaved by the ADAM-17 metalloprotease followed by an intramembrane cleavage mediated by gamma-secretase [38].

Regulatory relationships of NOTCH1

  • Strikingly, the PS1 L166P mutation not only induces an exceptionally high increase of Abeta(42) production but also impairs NICD production and Notch signaling, as well as AICD generation [39].
  • Thus, Dl-1 behaves as a functional ligand for Notch-1 and has the same ability to suppress cell differentiation as the Jagged proteins do [40].
  • Strikingly, blockade of Notch cleavage with a gamma secretase inhibitor failed to affect cytokine production in this system, implying that Delta1 can influence cytokine production via a Notch cleavage-independent mechanism [41].
  • In this study, over-expression and depletion of Notch-1 intracellular domain (NICD) strategies were used to investigate whether expression of the GAA gene is under the control of Notch-1/Hes-1 signaling [42].
  • We suggest that activation of Notch signaling may serve as an additional mechanism to inhibit wild-type p53 function in papillomavirus-associated neoplasia [43].
  • We show that NOTCH1 regulates the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells [44].

Other interactions of NOTCH1


Analytical, diagnostic and therapeutic context of NOTCH1

  • Interestingly, the statistically significant difference of survival according to NOTCH1 mutations was only observed in adult patients (>18 years) but not in pediatric patients (< or = 18 years), possibly due to the relatively good overall response of childhood T-ALL to the current chemotherapy [3].
  • Immunoprecipitation analyses with antibodies to both the intracellular forms of NOTCH1 and to RBP-Jkappa demonstrated that little or no RBP-Jkappa is associated with NOTCH1 in B cell lines compared to the RBP-Jkappa associated with NOTCH1 in T cell lines and was further demonstrated in human primary lymphocytes [49].
  • These results show that the CUTLL1 cell line has a strong dependence on NOTCH1 signaling for proliferation and survival and supports that T-ALL patients whose tumors harbor t(7;9) should be included in clinical trials testing the therapeutic efficacy NOTCH1 inhibition with GSIs [4].
  • By using a two-cell coculture assay, we show here that vertebrate Dl-1 activates the Notch-1 cascade [40].
  • The mRNA transcript levels of AAH, insulin receptor substrate (IRS), insulin and insulin-like growth factor (IGF) receptors and polypeptides, Notch, Jagged, and HES were measured in 15 paired samples of HCC and adjacent HCC-free human liver biopsy specimens using real-time quantitative RT-PCR and Western blot analysis [50].


  1. Identification of a conserved negative regulatory sequence that influences the leukemogenic activity of NOTCH1. Chiang, M.Y., Xu, M.L., Histen, G., Shestova, O., Roy, M., Nam, Y., Blacklow, S.C., Sacks, D.B., Pear, W.S., Aster, J.C. Mol. Cell. Biol. (2006) [Pubmed]
  2. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Reedijk, M., Odorcic, S., Chang, L., Zhang, H., Miller, N., McCready, D.R., Lockwood, G., Egan, S.E. Cancer Res. (2005) [Pubmed]
  3. NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in multifactorial leukemogenesis. Zhu, Y.M., Zhao, W.L., Fu, J.F., Shi, J.Y., Pan, Q., Hu, J., Gao, X.D., Chen, B., Li, J.M., Xiong, S.M., Gu, L.J., Tang, J.Y., Liang, H., Jiang, H., Xue, Y.Q., Shen, Z.X., Chen, Z., Chen, S.J. Clin. Cancer Res. (2006) [Pubmed]
  4. CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gamma-secretase inhibitors. Palomero, T., Barnes, K.C., Real, P.J., Bender, J.L., Sulis, M.L., Murty, V.V., Colovai, A.I., Balbin, M., Ferrando, A.A. Leukemia (2006) [Pubmed]
  5. NOTCH1-induced T-cell leukemia in transgenic zebrafish. Chen, J., Jette, C., Kanki, J.P., Aster, J.C., Look, A.T., Griffin, J.D. Leukemia (2007) [Pubmed]
  6. The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling. Malyukova, A., Dohda, T., von der Lehr, N., Akhoondi, S., Akhondi, S., Corcoran, M., Heyman, M., Spruck, C., Grandér, D., Lendahl, U., Sangfelt, O. Cancer Res. (2007) [Pubmed]
  7. NOTCH1 mutation can be an early, prenatal genetic event in T-ALL. Eguchi-Ishimae, M., Eguchi, M., Kempski, H., Greaves, M. Blood (2008) [Pubmed]
  8. Notch1 is an effector of Akt and hypoxia in melanoma development. Bedogni, B., Warneke, J.A., Nickoloff, B.J., Giaccia, A.J., Powell, M.B. J. Clin. Invest. (2008) [Pubmed]
  9. Processing of Notch and amyloid precursor protein by gamma-secretase is spatially distinct. Tarassishin, L., Yin, Y.I., Bassit, B., Li, Y.M. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  10. Progression of regulatory gene expression states in fetal and adult pro-T-cell development. David-Fung, E.S., Yui, M.A., Morales, M., Wang, H., Taghon, T., Diamond, R.A., Rothenberg, E.V. Immunol. Rev. (2006) [Pubmed]
  11. Notch signalling regulates stem cell numbers in vitro and in vivo. Androutsellis-Theotokis, A., Leker, R.R., Soldner, F., Hoeppner, D.J., Ravin, R., Poser, S.W., Rueger, M.A., Bae, S.K., Kittappa, R., McKay, R.D. Nature (2006) [Pubmed]
  12. Human Genetics. Notch, stroke and dementia. Gridley, T. Nature (1996) [Pubmed]
  13. Notch-1 immunoexpression is increased in Alzheimer's and Pick's disease. Nagarsheth, M.H., Viehman, A., Lippa, S.M., Lippa, C.F. J. Neurol. Sci. (2006) [Pubmed]
  14. Regulation of lymphoid development, differentiation, and function by the Notch pathway. Maillard, I., Fang, T., Pear, W.S. Annu. Rev. Immunol. (2005) [Pubmed]
  15. Regulation of T cell fate by Notch. Robey, E. Annu. Rev. Immunol. (1999) [Pubmed]
  16. Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Nam, Y., Sliz, P., Song, L., Aster, J.C., Blacklow, S.C. Cell (2006) [Pubmed]
  17. Regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by notch signaling. Nakakura, E.K., Sriuranpong, V.R., Kunnimalaiyaan, M., Hsiao, E.C., Schuebel, K.E., Borges, M.W., Jin, N., Collins, B.J., Nelkin, B.D., Chen, H., Ball, D.W. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  18. Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells. Stockhausen, M.T., Sjölund, J., Manetopoulos, C., Axelson, H. Br. J. Cancer (2005) [Pubmed]
  19. 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]
  20. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Breit, S., Stanulla, M., Flohr, T., Schrappe, M., Ludwig, W.D., Tolle, G., Happich, M., Muckenthaler, M.U., Kulozik, A.E. Blood (2006) [Pubmed]
  21. All-trans retinoid acid increases Notch1 transcript expression in acute promyelocytic leukemia. Lin, J.T., Wu, M.S., Wang, W.S., Yen, C.C., Chiou, T.J., Liu, J.H., Yang, M.H., Chao, T.C., Chou, S.C., Chen, P.M. Advances in therapy. (2003) [Pubmed]
  22. Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and NOTCH2. Capobianco, A.J., Zagouras, P., Blaumueller, C.M., Artavanis-Tsakonas, S., Bishop, J.M. Mol. Cell. Biol. (1997) [Pubmed]
  23. Oncogenic forms of NOTCH1 lacking either the primary binding site for RBP-Jkappa or nuclear localization sequences retain the ability to associate with RBP-Jkappa and activate transcription. Aster, J.C., Robertson, E.S., Hasserjian, R.P., Turner, J.R., Kieff, E., Sklar, J. J. Biol. Chem. (1997) [Pubmed]
  24. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Weng, A.P., Nam, Y., Wolfe, M.S., Pear, W.S., Griffin, J.D., Blacklow, S.C., Aster, J.C. Mol. Cell. Biol. (2003) [Pubmed]
  25. Mutations in NOTCH1 cause aortic valve disease. Garg, V., Muth, A.N., Ransom, J.F., Schluterman, M.K., Barnes, R., King, I.N., Grossfeld, P.D., Srivastava, D. Nature (2005) [Pubmed]
  26. Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes. Malecki, M.J., Sanchez-Irizarry, C., Mitchell, J.L., Histen, G., Xu, M.L., Aster, J.C., Blacklow, S.C. Mol. Cell. Biol. (2006) [Pubmed]
  27. Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Nefedova, Y., Cheng, P., Alsina, M., Dalton, W.S., Gabrilovich, D.I. Blood (2004) [Pubmed]
  28. The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells. Sade, H., Krishna, S., Sarin, A. J. Biol. Chem. (2004) [Pubmed]
  29. The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway. Sakamoto, K., Yamaguchi, S., Ando, R., Miyawaki, A., Kabasawa, Y., Takagi, M., Li, C.L., Perbal, B., Katsube, K. J. Biol. Chem. (2002) [Pubmed]
  30. Aspartate mutations in presenilin and gamma-secretase inhibitors both impair notch1 proteolysis and nuclear translocation with relative preservation of notch1 signaling. Berezovska, O., Jack, C., McLean, P., Aster, J.C., Hicks, C., Xia, W., Wolfe, M.S., Kimberly, W.T., Weinmaster, G., Selkoe, D.J., Hyman, B.T. J. Neurochem. (2000) [Pubmed]
  31. Regulation of the nuclear localization of the human Nedd4-related WWP1 protein by Notch. Flasza, M., Nguyen Huu, N.S., Mazaleyrat, S., Clémence, S., Villemant, C., Clarke, R., Baron, M. Mol. Membr. Biol. (2006) [Pubmed]
  32. WNT antagonist, DKK2, is a Notch signaling target in intestinal stem cells: Augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates. Katoh, M., Katoh, M. Int. J. Mol. Med. (2007) [Pubmed]
  33. Functional interaction between the mouse notch1 intracellular region and histone acetyltransferases PCAF and GCN5. Kurooka, H., Honjo, T. J. Biol. Chem. (2000) [Pubmed]
  34. Rapid Notch1 nuclear translocation after ligand binding depends on presenilin-associated gamma-secretase activity. Berezovska, O., Jack, C., McLean, P., Aster, J.C., Hicks, C., Xia, W., Wolfe, M.S., Weinmaster, G., Selkoe, D.J., Hyman, B.T. Ann. N. Y. Acad. Sci. (2000) [Pubmed]
  35. Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Wang, Z., Banerjee, S., Li, Y., Rahman, K.M., Zhang, Y., Sarkar, F.H. Cancer Res. (2006) [Pubmed]
  36. Immunohistological localization of Notch receptors and their ligands Delta and Jagged in synovial tissues of rheumatoid arthritis. Yabe, Y., Matsumoto, T., Tsurumoto, T., Shindo, H. Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. (2005) [Pubmed]
  37. Gamma-secretase exists on the plasma membrane as an intact complex that accepts substrates and effects intramembrane cleavage. Chyung, J.H., Raper, D.M., Selkoe, D.J. J. Biol. Chem. (2005) [Pubmed]
  38. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. Kimberly, W.T., Zheng, J.B., Guénette, S.Y., Selkoe, D.J. J. Biol. Chem. (2001) [Pubmed]
  39. Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Moehlmann, T., Winkler, E., Xia, X., Edbauer, D., Murrell, J., Capell, A., Kaether, C., Zheng, H., Ghetti, B., Haass, C., Steiner, H. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  40. Delta-1 activation of notch-1 signaling results in HES-1 transactivation. Jarriault, S., Le Bail, O., Hirsinger, E., Pourquié, O., Logeat, F., Strong, C.F., Brou, C., Seidah, N.G., Isra l, A. Mol. Cell. Biol. (1998) [Pubmed]
  41. Small interfering RNA-mediated knockdown of notch ligands in primary CD4+ T cells and dendritic cells enhances cytokine production. Stallwood, Y., Briend, E., Ray, K.M., Ward, G.A., Smith, B.J., Nye, E., Champion, B.R., McKenzie, G.J. J. Immunol. (2006) [Pubmed]
  42. 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]
  43. Activated Notch1 inhibits p53-induced apoptosis and sustains transformation by human papillomavirus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. Nair, P., Somasundaram, K., Krishna, S. J. Virol. (2003) [Pubmed]
  44. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Palomero, T., Sulis, M.L., Cortina, M., Real, P.J., Barnes, K., Ciofani, M., Caparros, E., Buteau, J., Brown, K., Perkins, S.L., Bhagat, G., Agarwal, A.M., Basso, G., Castillo, M., Nagase, S., Cordon-Cardo, C., Parsons, R., Zúñiga-Pflücker, J.C., Dominguez, M., Ferrando, A.A. Nat. Med. (2007) [Pubmed]
  45. F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation. Hu, Q.D., Ang, B.T., Karsak, M., Hu, W.P., Cui, X.Y., Duka, T., Takeda, Y., Chia, W., Sankar, N., Ng, Y.K., Ling, E.A., Maciag, T., Small, D., Trifonova, R., Kopan, R., Okano, H., Nakafuku, M., Chiba, S., Hirai, H., Aster, J.C., Schachner, M., Pallen, C.J., Watanabe, K., Xiao, Z.C. Cell (2003) [Pubmed]
  46. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. McDaniell, R., Warthen, D.M., Sanchez-Lara, P.A., Pai, A., Krantz, I.D., Piccoli, D.A., Spinner, N.B. Am. J. Hum. Genet. (2006) [Pubmed]
  47. Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Liu, Z.J., Shirakawa, T., Li, Y., Soma, A., Oka, M., Dotto, G.P., Fairman, R.M., Velazquez, O.C., Herlyn, M. Mol. Cell. Biol. (2003) [Pubmed]
  48. Notch1 signaling sensitizes tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human hepatocellular carcinoma cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. Wang, C., Qi, R., Li, N., Wang, Z., An, H., Zhang, Q., Yu, Y., Cao, X. J. Biol. Chem. (2009) [Pubmed]
  49. Intracellular forms of human NOTCH1 interact at distinctly different levels with RBP-jkappa in human B and T cells. Callahan, J., Aster, J., Sklar, J., Kieff, E., Robertson, E.S. Leukemia (2000) [Pubmed]
  50. Aspartyl-asparagyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms. Cantarini, M.C., de la Monte, S.M., Pang, M., Tong, M., D'Errico, A., Trevisani, F., Wands, J.R. Hepatology (2006) [Pubmed]
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