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Molecular and Cellular Biology, August 2006, p. 6261-6271, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.02478-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Identification of a Conserved Negative Regulatory Sequence That Influences the Leukemogenic Activity of NOTCH1

Mark Y. Chiang,1,{dagger} Mina L. Xu,2,{dagger} Gavin Histen,2 Olga Shestova,3 Monideepa Roy,2 Yunsun Nam,2 Stephen C. Blacklow,2 David B. Sacks,2 Warren S. Pear,3 and Jon C. Aster2*

Department of Hematology/Oncology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104,1 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115,2 Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 191043

Received 28 December 2005/ Returned for modification 8 February 2006/ Accepted 26 May 2006

NOTCH1 is a large type I transmembrane receptor that regulates normal T-cell development via a signaling pathway that relies on regulated proteolysis. Ligand binding induces proteolytic cleavages in NOTCH1 that release its intracellular domain (ICN1), which translocates to the nucleus and activates target genes by forming a short-lived nuclear complex with two other proteins, the DNA-binding factor CSL and a Mastermind-like (MAML) coactivator. 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. This region includes the highly conserved sequence WSSSSP (S4), which based on its amino acid content appeared to be a likely site for regulatory serine phosphorylation events. We show here that the mutation of the S4 sequence leads to hypophosphorylation of ICN1; increased NOTCH1 signaling; and the stabilization of complexes containing ICN1, CSL, and MAML1. 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. These studies indicate that S4 is an important negative regulatory sequence and that the deletion of S4 likely contributes to the development of human T-ALL.

* Corresponding author. Mailing address: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115. Phone: (617) 278-0032. Fax: (617) 264-5169. E-mail: jaster{at}rics.bwh.harvard.edu.

{dagger} M.Y.C. and M.L.X. contributed equally to this study.

Molecular and Cellular Biology, August 2006, p. 6261-6271, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.02478-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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