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Molecular and Cellular Biology, October 2000, p. 7505-7515, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Essential Roles for Ankyrin Repeat and Transactivation Domains in Induction of T-Cell Leukemia by Notch1

Jon C. Aster,1,* Lanwei Xu,2 Fredrick G. Karnell,2 Vytas Patriub,1 John C. Pui,2 and Warren S. Pear2,*

Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts,1 and Department of Pathology and Institute for Medicine and Engineering, University of Pennsylvania Medical School, Philadelphia, Pennsylvania2

Received 25 May 2000/Returned for modification 5 July 2000/Accepted 21 July 2000

Notch receptors participate in a conserved signaling pathway that controls the development of diverse tissues and cell types, including lymphoid cells. Signaling is normally initiated through one or more ligand-mediated proteolytic cleavages that permit nuclear translocation of the intracellular portion of the Notch receptor (ICN), which then binds and activates transcription factors of the Su(H)/CBF1 family. Several mammalian Notch receptors are oncogenic when constitutively active, including Notch1, a gene initially identified based on its involvement in a (7;9) chromosomal translocation found in sporadic T-cell lymphoblastic leukemias and lymphomas (T-ALL). To investigate which portions of ICN1 contribute to transformation, we performed a structure-transformation analysis using a robust murine bone marrow reconstitution assay. Both the ankyrin repeat and C-terminal transactivation domains were required for T-cell leukemogenesis, whereas the N-terminal RAM domain and a C-terminal domain that includes a PEST sequence were nonessential. Induction of T-ALL correlated with the transactivation activity of each Notch1 polypeptide when fused to the DNA-binding domain of GAL4, with the exception of polypeptides deleted of the ankyrin repeats, which lacked transforming activity while retaining strong transactivation activity. Transforming polypeptides also demonstrated moderate to strong activation of the Su(H)/CBF1-sensitive HES-1 promoter, while polypeptides with weak or absent activity on this promoter failed to cause leukemia. These experiments define a minimal transforming region for Notch1 in T-cell progenitors and suggest that leukemogenic signaling involves recruitment of transcriptional coactivators to ICN1 nuclear complexes.

* Corresponding author. Mailing address for Jon C. Aster: Department of Pathology, Brigham and Women's Hospital, Boston MA 02115. Phone: (617) 732-7483. Fax: (617) 732-7449. E-mail: jaster{at}rics.bwh.harvard.edu. Mailing address for Warren S. Pear: Department of Pathology and Institute for Medicine and Engineering, University of Pennsylvania Medical School, Philadelphia, PA 19104. Phone: (215) 573-7764. Fax: (215) 573-8606. E-mail: wpear{at}mail.med.upenn.edu.

Molecular and Cellular Biology, October 2000, p. 7505-7515, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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