Frequent provirus insertional mutagenesis of Notch1 in thymomas of MMTVD/myc transgenic mice suggests a collaboration of c-myc and Notch1 for oncogenesis

L Girard, Z Hanna, N Beaulieu, C D Hoemann, C Simard, C A Kozak, P Jolicoeur
1996 Genes & Development  
The MMTVD/myc transgenic mice spontaneously develop oligoclonal CD4+CD8 + T-ceU tumors. We used provirus insertional mutagenesis in these mice to identify putative collaborators of c-myc. We found that Notchl was mutated in a high proportion (52%) of these tumors. Proviruses were inserted upstream of the exon coding for the transmembrane domain and in both transcriptional orientations. These mutations led to high expression of truncated Notchl RNAs and proteins (86-110 kD). In addition, many
more » ... chl-rearranged tumors showed elevated levels of full-length Notchl transcripts, whereas nearly all showed increased levels of full-length (330-kD) or close to full-length (280-kD) Notchl proteins. The 5' end of the truncated RNAs were determined for some tumors by use of RT-PCR and 5' RACE techniques. Depending on the orientation of the proviruses, viral LTR or cryptic promoters appeared to be utilized, and coding potential began in most cases in the transmembrane domain. Pulse-chase experiments revealed that the 330-kD Notchl proteins were processed into 110-and 280-kD cleavage products. These results suggest that Notchl can be a frequent collaborator of c-myc for oncogenesis. Furthermore, our data indicate that Notchl alleles mutated by provirus insertion can lead to increased expression of truncated and full-length (330/280-kD) Notchl proteins, both being produced in a cleaved and uncleaved form. [Downloaded from Access the most recent version at doi: 10: 1996, Genes Dev. L Girard, Z Hanna, N Beaulieu, et al. Notch1 for oncogenesis. MMTVD/myc transgenic mice suggests a collaboration of c-myc and Frequent provirus insertional mutagenesis of Notch1 in thymomas of References http://genesdev.cshlp.org/content/10/15/1930.full.html#ref-list-1
doi:10.1101/gad.10.15.1930 pmid:8756350 fatcat:attpgdz3mze6bkpb3ynpaus7gm