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Molecular and Cellular Biology, June 2000, p. 3831-3842, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Two Distinct Notch1 Mutant Alleles Are Involved in the Induction of T-Cell Leukemia in c-myc Transgenic Mice

C. D. Hoemann,1,dagger N. Beaulieu,1,Dagger L. Girard,1,§ N. Rebai,1 and P. Jolicoeur1,2,3,*

Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7,1 Department of Microbiology and Immunology, Université de Montréal, Montreal, Quebec H3C 3J7,2 and Experimental Medicine, McGill University, Montreal, Quebec H3G 1A4,3 Canada

Received 29 November 1999/Returned for modification 8 January 2000/Accepted 10 February 2000

We have previously characterized a large panel of provirus insertion Notch1 mutant alleles and their products arising in thymomas of MMTVD/myc transgenic mice. Here, we show that these Notch1 mutations represent two clearly distinct classes. In the first class (type I), proviral integrations were clustered just upstream of sequences encoding the transmembrane domain. Type I Notch1 alleles produced two types of mutant Notch1 RNA, one of which encoded the entire Notch1 cytoplasmic domain [N(IC)] and the other of which encoded a soluble ectodomain [N(EC)Mut] which, in contrast to the processed wild-type ectodomain [N(EC)WT], did not reside at the cell surface and became secreted in a temperature-dependent manner. A second, novel class of mutant Notch1 allele (type II) encoded a Notch1 receptor with the C-terminal PEST motif deleted (Delta CT). The type II Notch1Delta CT protein was expressed as a normally processed receptor [N(EC)WT and N(IC)Delta CT] at the cell surface, and its ectodomain was found to be shed into the extracellular medium in a temperature- and calcium-dependent manner. These data suggest that both type I and type II mutations generate two structurally distinct Notch1 N(EC) and N(IC) proteins that may participate in tumor formation, in collaboration with the c-myc oncogene, through distinct mechanisms. Constitutive type I N(IC) and type II N(IC)Delta CT expression may enhance Notch1 intracellular signaling, while secreted or shed type I N(EC)Mut and type II N(EC) proteins may differentially interact in an autocrine or paracrine fashion with ligands of Notch1 and affect their signaling.

* Corresponding author. Mailing address: Clinical Research Institute of Montreal, 110 Pine Ave. West, Montreal, Québec, Canada H2W 1R7. Phone: (514) 987-5569. Fax: (514) 987-5794. E-mail: jolicop{at}ircm.qc.ca.

dagger Present address: BIOSYNTECH, Laval, Quebec, Canada H7V 4A7.

Dagger Present address: MethylGene, St. Laurent, Quebec, Canada H4S 2A1.

§ Present address: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75235-8593.

Molecular and Cellular Biology, June 2000, p. 3831-3842, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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