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The Journal of Immunology, 1999, 162: 635-638.
Copyright © 1999 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Protective Effects of Notch-1 on TCR-Induced Apoptosis1

Birgit M. Jehn*,{dagger}, Wolfgang Bielke*,{ddagger}, Warren S. Pear§ and Barbara A. Osborne2,*

* Department of Veterinary and Animal Sciences, Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, MA 01003; {dagger} Ruprecht-Karls-University of Heidelberg, Institute of Immunology, Heidelberg, Germany; {ddagger} Friedrich-Alexander-University of Erlangen/Nuremberg, Institute of Experimental Medicine, Erlangen, Germany; and § Department of Pathology and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The Notch receptor protein was originally identified in Drosophila and is known to mediate cell to cell communication and influence cell fate decisions. Members of this family have been isolated from invertebrates as well as vertebrates. We isolated mouse Notch-1 in a yeast two-hybrid screen with Nur77, which is a protein that has been shown previously to be required for apoptosis in T cell lines. The data presented below indicate that Notch-1 expression provides significant protection to T cell lines from TCR-mediated apoptosis. These data demonstrate a new antiapoptotic role for Notch-1, providing evidence that, in addition to regulating cell fate decisions, Notch-1 can play a critical role in controlling levels of cell death in T cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Tcell receptor (TCR)-dependent apoptosis in T cell lines requires the expression of members of the Nur77 orphan nuclear hormone receptor family (1, 2). It has been demonstrated previously that the specific blockade of Nur77 expression is sufficient to inhibit the apoptosis of T cells in cell culture as well as of maturing thymocytes in the thymus (3).

In an attempt to determine how Nur77 mediates apoptosis in T cell lines, we performed a yeast two-hybrid screen using a transcriptionally inert form of Nur77 as bait. This screen identified the transmembrane receptor protein Notch-1 as the interaction partner of Nur77. Notch proteins are important for the regulation of cell fate decisions and are characterized by an extracellular domain containing multiple epidermal growth factor-like repeats and an intracellular domain containing an ankyrin-repeat region (4). Notch-dependent signal transduction involves a ligand-dependent proteolytic cleavage of Notch, resulting in the release and translocation of its intracellular domain to the nucleus, where it is able to regulate gene transcription (reviewed in 5 .

Activated forms of Notch or Notch-like proteins are often associated with tumorigenic phenotypes in mammals. Translocation-associated notch homologue-1 (TAN-1)3, the human homologue of mouse Notch-1, is rearranged in some human T cell lymphomas (T cell acute lymphoblastic leukemia) bearing a t(7;9)(q34;q34.39) chromosomal translocation. This rearrangement results in a constitutively active, oncogenic protein lacking the extracellular domain (6). Int-3/Notch-4, another Notch-related protein, is found to be truncated by the insertion of mouse mammary tumor virus, resulting in the formation of breast tumors in mice exposed to this virus; insertion of this truncated form of Notch-4 is sufficient to cause mammary gland tumors (7).

Here, we report the novel observations that the nuclear receptor protein Nur77 and the transmembrane receptor Notch-1 interact physically and that Notch-1 protects from Nur77-dependent cell death in T cell lines. The data presented provide strong evidence that Notch-1 is a key player in nuclear hormone receptor-mediated cell death processes in vertebrates and suggest a new role for Notch-1 as an antiapoptotic protein.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Yeast two-hybrid screen

A transcriptionally inert but nuclear form of Nur77 (amino acids 268–536) was inserted into the bait vector pEG202 and transformed into the yeast strain EGY48/pSH18–34 (8, 9). Interactor clones were isolated by screening 6 x 106 colonies of a mouse T cell lymphoma cDNA library (Clontech, Palo Alto, CA). cDNA fragments of 55 interactor clones were analyzed. Retransformation of different bait and prey constructs into control yeast strains was performed as described previously (8, 9).

In vitro protein binding assay

A full-length Nur77 cDNA fragment was fused to a glutathione S-transferase (GST) tag (Pharmacia, Uppsala, Sweden). Protein purification from bacteria and coupling to GST-Sepharose beads was performed as described previously (10). COS-1 cells were transiently transfected, and extracts were prepared (10). GST-Nur77 protein coupled to beads was incubated with either buffer alone or the indicated extracts. Samples were washed six times and subjected to SDS-PAGE analysis.

Cell death induction and analysis

DO11.10 cells and retrovirally infected derivatives were plated at a density of 1.5 x 105 cells/ml and stimulated to die apoptotically as indicated. At 16–18 h postinduction, cells were stained with YOPRO-3-iodide (Molecular Probes, Eugene, OR) and analyzed using a FACScan.

Retroviral infection

Retroviral infections were performed as described previously (11). The retroviral constructs pGD-ICT and pGD-ECT+ and the empty retroviral vector MSCV2.1 were transiently transfected into Bosc 23 cells. DO11.10 cells were infected with retroviral particles for 24 h. G418 selection (1 µg/ml) was started at 24 h postinfection and was maintained throughout propagation of the infected cells. Apoptosis was induced as described previously.

Transient transfections and luciferase (Luc) reporter assays

A triple repeat of the Nur77-specific DNA response element (NurRE) was subcloned 5' of a thymidine kinase-Luc reporter gene. Transient cotransfections of 1.2 x 105 COS-1 cells/well were performed in 6-well plates using SuperFect reagent (Qiagen, Chatsworth, CA) and a total amount of 4.5 µg of plasmid DNA per well (1.5 µg of each plasmid DNA). Cellular extracts were prepared, and samples were analyzed at 24 h posttransfection for Luc activity according to the manufacturer’s instructions (Promega, Madison, WI). Transfections were normalized for the level of total cellular protein (Bradford Assay; Bio-Rad, Hercules, CA), and Luc activity was calculated per microgram of protein. Mean values and SDs are shown for at least four independent experiments (each done in duplicate).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Yeast two-hybrid system reveals that Notch-1 interacts with Nur77

Using the yeast two-hybrid system (8, 9), a transcriptionally inert form of Nur77 that was able to enter the nucleus was used as bait to screen a mouse T cell lymphoma cDNA library. Among 55 independently isolated interactor clones, 48 clones encoded the mouse Notch-1 protein. The majority of the clones that were isolated contained a region encoding the Notch-1 ankyrin-like repeats (12, 13), suggesting that the observed interaction with Nur77 occurs via this protein motif. To confirm the specificity of the interaction between Nur77 and Notch-1, various control experiments were conducted. Retransformation of either different or unrelated bait constructs as well as the reintroduction of both bait and prey constructs alone into different control yeast strains verified the specificity of the observed original interaction (Fig. 1GoA) and indicated that Nur77 and Notch-1 form a protein complex in yeast.



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  		FIGURE 1. Notch-Nur77 protein interactions. A, Summary of protein interactions in yeast. Activation of a LacZ reporter gene is only detected when pGAL4 is fused to Notch-1 and cotransfected with a pLexA-Nur77 plasmid indicating the specificity of the interaction. B, Western blot analysis (15 ) using the FlagM2 mAb (10 µg/ml) (Kodak, Rochester, NY). A GST-Nur77 fusion protein coupled to GST-Sepharose beads was incubated with either NETN buffer alone (150 mM NaCl, 1mM EDTA, 20 mM Tris, and 0.5% Nonidet p-40) (lane 1), whole cell extracts derived from COS-1 cells that had been transiently transfected with a Flag-tagged Notch-1 construct (lane 2), COS-1/Flag-tagged Notch-1 whole cell extracts plus 1 µg of purified Nur77 protein derived from a baculovirus insect cell expression system (PharMingen, San Diego, CA) (lane 3), or whole cell extracts derived from untransfected COS-1 cells (lane 4). Whole cell extracts derived from either Flag-tagged Notch-1-transfected COS-1 cells (lane 5) or untransfected COS-1 cells (lane 6) were loaded in the absence of GST-Nur77. M represents the biotinylated low range protein standard (Bio-Rad).

 
To test whether Nur77 can also interact with Notch-1 in cellular extracts, we confirmed a direct protein interaction between Nur77 and Notch-1 using an in vitro protein binding assay (Fig. 1GoB). A bacterially expressed and purified GST-Nur77 fusion protein was coupled to GST-Sepharose beads and mixed with whole cell extracts derived from either untransfected or Flag-tagged Notch-1 transfected COS-1 cells. In addition, GST-Nur77 was incubated with Flag-Notch-1-containing extracts and purified Nur77 protein derived from a baculovirus insect cell expression system. After formation of specific protein complexes, the samples were analyzed by Western blotting using the FlagM2 mAb (Fig. 1GoB). A specific complex was detected only in the presence of both interacting proteins and was slightly reduced in the presence of purified Nur77 protein, confirming that Nur77 interacts with Notch-1 in cellular extracts (Fig. 1GoB).

Retrovirally overexpressed forms of TAN-1 protect from Nur77-dependent cell death

To investigate Notch-1 function in lymphoid cells, we retrovirally infected different forms of the TAN-1 protein (Fig. 2Go), the human homologue of Notch-1 (6), in the T hybridoma cell line DO11.10. DO11.10 cells are a commonly used model of T cell death. DO11.10 cells do not express endogenous Notch-1. The cytoplasmic construct extracellular domain-containing form of TAN-1 (ECT+) contains parts of the extracellular domain and the complete transmembrane and intracellular domains of TAN-1, resulting in a 120-kDa protein (11) (Fig. 2Go). The nuclear construct intracellular domain of TAN-1 (ICT) encodes a 110-kDa protein containing only the intracellular domain (11). Retroviral expression of both constructs was confirmed by Western blot analysis using the bTAN18 mAb (data not shown). To exclude any nonspecific, long terminal repeat-derived effects on the parental cell line DO11.10, the empty retroviral vector MSCV2.1 was introduced into these cells.



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  		FIGURE 2. TAN-1 constructs. The presented TAN-1 constructs were used for retroviral infection of DO11.10 cells. Infected cells were selected with G418 (1 mg/ml) and grown in G418-containing medium through further propagation. TM, transmembrane domain; ANK, ankyrin-repeat domain.

 
We subsequently compared apoptotic cell death in TAN-1-expressing cells vs control cells. Apoptosis induced via TCR cross-linking or treatment with PMA/CaI or dexamethasone leads to similar levels of cell death in both the parental cell line DO11.10 and the MSCV2.1-infected control line (Fig. 3GoA). In contrast, DO11.10 cells expressing ECT+ or ICT are protected from the Nur77-dependent apoptosis induced via TCR cross-linking or PMA/CaI treatment (Fig. 3GoB). Protection in the range of ~45–60% was observed with the different constructs compared with uninfected or MSCV2.1-infected DO11.10 cells.



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  		FIGURE 3. Effects of retrovirally infected forms of TAN-1 on apoptosis in DO11.10 cells. DO11.10 cells were cultured in RDG medium RPMI 1640 plus DMEM mixed 1:1) containing 10% horse serum. For cell death induction and analysis, cells were plated at a density of 1–2 x 105 cells/ml and stimulated either with a combination of 10 nM of PMA and 500 nM of CaI A23187 or with 20 µM of dexamethasone. For TCR cross-linking, DO11.10 cells were plated in a cell culture flask coated with the mAb F23.1, which specifically interacts with the Vß8 chain present on DO11.10 cells. A, FACScan analysis of DO11.10 cells or empty retroviral vector-infected MSCV2.1 cells that had been induced to die apoptotically either with the TCR-specific Ab F23.1, with a combination of 10 nM of PMA and 500 nM of CaI, or with 20 µM dexamethasone. YO-PRO-3 iodide-stained cells were analyzed at 16–18 h poststimulation by FACScan. B, Expression of pGD-ICT and pGD-ECT+ protects cells from F23.1- and PMA/CaI-induced apoptosis. Cells were induced and analyzed as described previously. C, Expression of pGD-ICT and pGD-ECT+ does not affect dexamethasone-induced cell death. Cells were treated with 20 µM of dexamethasone and analyzed at 16–18 h poststimulation as described in A.

 
To investigate whether the protection conferred by Notch-1 was specific for Nur77 signaling pathways, we subsequently examined the effect of Notch-1 on glucocorticoid-induced death, an event that does not require Nur77 (1). Cell death initiated with dexamethasone remains unaffected and is equivalent in TAN-1-expressing cells and MSCV2.1-infected cells (Fig. 3GoC). Therefore, Notch-1-mediated protection from cell death is dependent upon the presence of Nur77 and most likely on the physical interaction with this nuclear hormone receptor protein.

To determine where Notch-1 is found in T cells, subcellular localization of ICT and ECT+ proteins was determined in DO11.10 cells signaled to undergo apoptosis after combinatorial PMA/CaI treatment. In Fig. 4GoA, the results of Western blots of nuclear extracts demonstrate that ICT is found exclusively in the nucleus, whereas ECT+ is first expressed in the cytosol and, after 2 h, translocates to the nucleus. Data are summarized in Fig. 4GoB.



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  		FIGURE 4. TAN-1 protein is found in the nucleus and impairs Nur77-dependent transcription. DO11.10 cells were stimulated with PMA (10 nM) and CaI (500 nM) and assayed at 0, 2, 4, and 8 h poststimulation. At each timepoint, nuclear extracts were prepared and run on SDS-PAGE. A total of 15 µg of nuclear protein was loaded per lane. The proteins were transferred and probed with the bTAN18 mAb. ECT+ and TANFull were not detectable in nuclear extracts at 0 and 2 h but were detectable by 4 h, indicating that these forms of the protein are initially cytoplasmic and are subsequently translocated into the nucleus. All other forms of TAN were immediately detectable in the nucleus. A, Western blots of the 0 and 4 h timepoints; B, Summary of the data at all timepoints. C, Cotransfected forms of TAN-1 impair Nur77-dependent promoter activity. A total of 1.2 x 105 COS-1 cells were cotransfected using a total amount of 4.5 µg of plasmid DNA. Cotransfection of a NurRE-thymidine kinase (TK)-Luc construct and a Nur77 expression plasmid leads to a strong induction of Luc activity (black). Additional cotransfection of either an ICT expression plasmid (light gray) or a ECT+ expression plasmid (dark gray) results in an impairment of Nur77-dependent promoter activity.

 
To demonstrate that TAN-1 directly influences Nur77 function, we cotransfected a Nur77 Luc reporter construct with an expression construct of Nur77. As shown in Fig. 4GoC, Nur77 expression drives the Luc reporter, and this induction was dramatically impaired in the presence of cotransfected TAN-1 protein, indicating that TAN-1 directly modulates the functional activity of Nur77. These data support the conclusion that Notch expression alters Nur77 activity.

The proposed complex formation between Nur77 and Notch-1 and the observed suppression of cell death in T cells might have unique implications in the context of neoplasia and tumor formation. In this regard, it is interesting to note that during normal thymic development, Notch-1 expression is observed in early CD4-/CD8- T cells and is significantly reduced in CD4+/CD8+ T cells undergoing negative selection (14). Recently, it was observed that Nur77 is expressed in both CD4-/CD8- double-negative and CD4+/CD8+ double-positive thymocytes (K. Fortner, K. Newell, and B.A.O., unpublished observations), suggesting that Notch-1 might be involved in protecting double-negative thymocytes from cell death while the decrease in Notch-1 levels in double-positive thymocytes renders them sensitive to TCR-mediated death. Therefore, it is possible that after the development of double-negative thymocytes, Nur77 and Notch-1 are not expressed simultaneously in a normal context. However, in those situations in which Nur77 and Notch-1 are inappropriately coexpressed, we propose that this interaction provides protection from the normal cell death pathway operating during thymic development. These observations have important implications for our understanding of tumorigenesis in lymphoid cells. Pear et al. (11) demonstrated recently that expression of different TAN-1 alleles in hemopoietic cell types correlates with tumor formation. In a bone marrow reconstitution assay with TAN-1-expressing cells, T cell leukemias were induced (11). In all cases, the T cell neoplasms were of an immature phenotype and phenotypically resembled tumors caused by endogenous murine TAN-1. In this context, it appears that TAN-1 is oncogenic for T cells (11).

In conclusion, the data presented in this paper demonstrate an interaction between Nur77 and Notch-1. The functional consequences of Notch-1 expression are twofold. First, TAN-1 can inhibit Nur77-dependent cell death. Second, the expression of TAN-1 protein leads to reduced activity of the Nur77 reporter gene, indicating that TAN-1 represses Nur77 function. These data support a model whereby Nur77-dependent apoptosis is inhibited by Notch-1 through direct protein binding and subsequent inhibition of Nur77 transcriptional activity.


   Acknowledgments
 
We thank R. Brent and coworkers for sharing the yeast strain EGY48 and various plasmid constructs for the yeast two-hybrid screen, E. Robey for providing the Flag-tagged Notch-1 construct, J. Aster for providing retroviral TAN constructs, and S. Artavanis-Tsakonas for sharing the bTAN18 mAb. B.M.J. thanks Stefan Meuer for his advice and support.


   Footnotes
 
1 B.M.J. and W.B were supported by the Deutsche Forschungsgemeinschaft and the National Institutes of Health. B.M.J. is currently supported by a stipend from the German Cancer Research Center (DKFZ). W.S.P. is a Special Fellow of the Leukemia Society of America and the recipient of a Penn/Hughes Scientist Award. B.A.O. is supported by the National Institutes of Health (GM479922) and the American Cancer Society (IM-759). Back

2 Address correspondence and reprint requests to Dr. Barbara A. Osborne, Department of Veterinary and Animal Sciences, 311 Paige Lab, University of Massachusetts, Amherst, MA 01003. Back

3 Abbreviations used in this paper: TAN, translocation-associated notch homologue; ICT, intracellular domain of TAN-1; ECT+, extracellular domain containing form of TAN-1; GST, glutathione S-transferase; Luc, luciferase. Back

Received for publication September 24, 1998. Accepted for publication November 6, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Liu, Z. G., S. W. Smith, K. A. McLaughlin, L. M. Schwartz, B. A. Osborne. 1994. Apoptotic signals delivered through the T cell receptor require the immediate early gene nur77. Nature 367:281.[Medline]
  2. Woronicz, J. D., B. Calnan, V. Ngo, A. Winoto. 1994. Requirement for the orphan receptor Nur77 in apoptosis of T cell hybridomas. Nature 367:277.[Medline]
  3. Winoto, A.. 1997. Cell death in the regulation of immune responses. Curr. Opin. Immunol. 9:365.[Medline]
  4. Artavanis-Tsakonas, S., K. Matsuno, M. E. Fortini. 1995. Notch signaling. Science 268:225.[Abstract/Free Full Text]
  5. Chan, Y. M., Y. N. Jan. 1998. Roles for proteolysis and trafficking in notch maturation and signal transduction. Cell 94:423.[Medline]
  6. Ellisen, L. W., J. Bird, D. C. West, A. L. Soreng, T. C. Reynolds, S. D. Smith, J. Sklar. 1991. TAN1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in lymphoblastic neoplasms. Cell 66:649.[Medline]
  7. Jhappan, C., D. Gallahan, C. Stahle, E. Chu, G. H. Smith, G. Merlino, R. Callahan. 1992. Expression of an activated Notch-related int3 transgene interferes with cell differentiation and induces neoplastic transformation in the mammary and the salivary glands. Genes Dev. 6:345.[Abstract/Free Full Text]
  8. Gyuris, J., E. Golemis, H. Chertkov, R. Brent. 1993. Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2. Cell 75:791.[Medline]
  9. Zervos, A. S., J. Gyuris, R. Brent. 1993. Mxi1, a protein that specifically interacts with Max to bind MycMax recognition sites. Cell 72:223.[Medline]
  10. Lee, M. S., S. Ogg, M. Xu, L. L. Parker, D. J. Donoghue, L. Maller, H. Piwnica-Worms. 1992. Cdc25+ encodes a protein phosphatase that dephosphorylates p34cdc2. Mol. Biol. Cell 13:73.
  11. Pear, W. S., J. C. Aster, M. L. Scott, R. P. Hasserjian, B. Soffer, J. D. Sklar, D. Baltimore. 1996. Exclusive development of T cell neoplasms in mice transplanted with bone marrow-expressing activated Notch alleles. J. Exp. Med. 83:2283.
  12. Breeden, L., K. Nasmyth. 1987. Similarity between the cell cycle genes of the budding yeast and fission yeast and the Notch gene of Drosophila. Nature 329:651.[Medline]
  13. Lux, S. E., K. M. John, V. Bennett. 1990. Analysis of cDNA for human erythrocyte ankyrin indicates a repeated structure with homology to tissue-differentiation and cell-cycle proteins. Nature 344:36.[Medline]
  14. Hasserjian, R., J. Aster, D. Davi, D. Weinberg, J. Sklar. 1996. Modulated expression of Notch-1 during thymocyte development. Blood 88:970.[Abstract/Free Full Text]
  15. Harlow, E., D. Lane. 1988. Antibodies: A Laboratory Manual Cold Spring Harbor Press, Cold Spring Harbor, NY.



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H. Chen, L. Hutt-Fletcher, L. Cao, and S. D. Hayward
A Positive Autoregulatory Loop of LMP1 Expression and STAT Activation in Epithelial Cells Latently Infected with Epstein-Barr Virus
J. Virol., April 1, 2003; 77(7): 4139 - 4148.
[Abstract] [Full Text] [PDF]

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 Mol. Biol. CellHome page
L. Espinosa, J. Ingles-Esteve, A. Robert-Moreno, and A. Bigas
Ikappa Balpha and p65 Regulate the Cytoplasmic Shuttling of Nuclear Corepressors: Cross-talk between Notch and NFkappa B Pathways
Mol. Biol. Cell, February 1, 2003; 14(2): 491 - 502.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
A. P. Weng, Y. Nam, M. S. Wolfe, W. S. Pear, J. D. Griffin, S. C. Blacklow, and J. C. Aster
Growth Suppression of Pre-T Acute Lymphoblastic Leukemia Cells by Inhibition of Notch Signaling
Mol. Cell. Biol., January 15, 2003; 23(2): 655 - 664.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
J. M. Lee, K.-H. Lee, M. Weidner, B. A. Osborne, and S. D. Hayward
Epstein-Barr virus EBNA2 blocks Nur77- mediated apoptosis
PNAS, September 3, 2002; 99(18): 11878 - 11883.
[Abstract] [Full Text] [PDF]

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 BloodHome page
M. Dorsch, G. Zheng, D. Yowe, P. Rao, Y. Wang, Q. Shen, C. Murphy, X. Xiong, Q. Shi, J.-C. Gutierrez-Ramos, et al.
Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease
Blood, August 28, 2002; 100(6): 2046 - 2055.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
B. J. Fowlkes and E. A. Robey
A Reassessment of the Effect of Activated Notch1 on CD4 and CD8 T Cell Development
J. Immunol., August 15, 2002; 169(4): 1817 - 1821.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
S. Jeffries, D. J. Robbins, and A. J. Capobianco
Characterization of a High-Molecular-Weight Notch Complex in the Nucleus of Notchic-Transformed RKE Cells and in a Human T-Cell Leukemia Cell Line
Mol. Cell. Biol., June 1, 2002; 22(11): 3927 - 3941.
[Abstract] [Full Text] [PDF]

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 Int ImmunolHome page
H. Han, K. Tanigaki, N. Yamamoto, K. Kuroda, M. Yoshimoto, T. Nakahata, K. Ikuta, and T. Honjo
Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision
Int. Immunol., June 1, 2002; 14(6): 637 - 645.
[Abstract] [Full Text] [PDF]

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 BloodHome page
F. Jundt, I. Anagnostopoulos, R. Forster, S. Mathas, H. Stein, and B. Dorken
Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma
Blood, May 1, 2002; 99(9): 3398 - 3403.
[Abstract] [Full Text] [PDF]

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 J. Cell Sci.Home page
L. Espinosa, S. Santos, J. Ingles-Esteve, P. Munoz-Canoves, and A. Bigas
p65-NF{kappa}B synergizes with Notch to activate transcription by triggering cytoplasmic translocation of the nuclear receptor corepressor N-CoR
J. Cell Sci., March 15, 2002; 115(6): 1295 - 1303.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
S. Kawamata, C. Du, K. Li, and C. Lavau
Notch1 Perturbation of Hemopoiesis Involves Non-Cell- Autonomous Modifications
J. Immunol., February 15, 2002; 168(4): 1738 - 1745.
[Abstract] [Full Text] [PDF]

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 Stem CellsHome page
L. Walker, A. Carlson, H. T. Tan-Pertel, G. Weinmaster, and J. Gasson
The Notch Receptor and Its Ligands Are Selectively Expressed During Hematopoietic Development in the Mouse
Stem Cells, November 1, 2001; 19(6): 543 - 552.
[Abstract] [Full Text]

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 Mol. Cell. Biol.Home page
J. Dang, T. Inukai, H. Kurosawa, K. Goi, T. Inaba, N. T. Lenny, J. R. Downing, S. Stifani, and A. T. Look
The E2A-HLF Oncoprotein Activates Groucho-Related Genes and Suppresses Runx1
Mol. Cell. Biol., September 1, 2001; 21(17): 5935 - 5945.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
P. Doerfler, M. S. Shearman, and R. M. Perlmutter
Presenilin-dependent gamma -secretase activity modulates thymocyte development
PNAS, July 19, 2001; (2001) 161102498.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
J. Wang, L. Shelly, L. Miele, R. Boykins, M. A. Norcross, and E. Guan
Human Notch-1 Inhibits NF-{{kappa}}B Activity in the Nucleus Through a Direct Interaction Involving a Novel Domain
J. Immunol., July 1, 2001; 167(1): 289 - 295.
[Abstract] [Full Text] [PDF]

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 J. Virol.Home page
H. Höfelmayr, L. J. Strobl, G. Marschall, G. W. Bornkamm, and U. Zimber-Strobl
Activated Notch1 Can Transiently Substitute for EBNA2 in the Maintenance of Proliferation of LMP1-Expressing Immortalized B Cells
J. Virol., March 1, 2001; 75(5): 2033 - 2040.
[Abstract] [Full Text]

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