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

doi:10.1128/MCB.20.11.3831-3842.2000

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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^, N. Beaulieu,¹^, 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 thymomasof MMTV^D/myc transgenic mice. Here, we show that these Notch1 mutationsrepresent two clearly distinct classes. In the first class (typeI), proviral integrations were clustered just upstream of sequencesencoding the transmembrane domain. Type I Notch1 alleles producedtwo types of mutant Notch1 RNA, one of which encoded the entireNotch1 cytoplasmic domain [N(IC)] and the other of which encodeda 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 atemperature-dependent manner. A second, novel class of mutantNotch1 allele (type II) encoded a Notch1 receptor with the C-terminalPEST motif deleted ( $Delta$ CT). The type II Notch1^CT protein was expressed as a normally processed receptor [N(EC)^WT and N(IC)^CT] at the cell surface, and its ectodomain was found to be shedinto the extracellular medium in a temperature- and calcium-dependentmanner. These data suggest that both type I and type II mutationsgenerate two structurally distinct Notch1 N(EC) and N(IC) proteinsthat may participate in tumor formation, in collaboration withthe c-myc oncogene, through distinct mechanisms. Constitutivetype I N(IC) and type II N(IC)^CT expression may enhance Notch1 intracellular signaling, whilesecreted or shed type I N(EC)^Mut and type II N(EC) proteins may differentially interact in anautocrine or paracrine fashion with ligands of Notch1 and affecttheirsignaling.

^* Corresponding author. Mailing address: Clinical Research Institute of Montreal, 110 Pine Ave. West, Montreal, Québec, CanadaH2W 1R7. Phone: (514) 987-5569. Fax: (514) 987-5794. E-mail: jolicop{at}ircm.qc.ca.

Present address: BIOSYNTECH, Laval, Quebec, Canada H7V4A7.

Present address: MethylGene, St. Laurent, Quebec, Canada H4S2A1.

^§ 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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