ACTIVATION OF THE NUCLEAR ONCOGENES N-MYC AND C-JUN IN CARTINOID TUMORS OF TRANSGENIC MICE CARRYING THE HUMAN ADENOVIRUS-TYPE-12 E1 REGION GENE

The adenovirus (Ad) El region genes, EIA and E1B, are well known coope ratively to transform primary rodent cells and activate a number of ce llular promoters, including nuclear oncogenes such as N-myc and c-jun, in transfected cell lines. However, there is still less information a vailable on the in vivo mechanism(s) by which the El region gene, when chromosomally integrated ill the living animals, exerts its effect on nuclear oncogene activation coupled with transformation. To investiga te such in vivo activity of E1A we have used a series of microinjectio n experiments into fertilized eggs to generate three transgenic mice c arrying the Ad12-type E1A/E1B genes under the control of the human ren in gene, This transgene caused an early onset of bowel cartinoid tumor s that express neural cell adhesion molecules, but do not metastasize to any region. Northern blot analysis revealed that the transgenes wer e considerably expressed in the tumors, but not in other tissues at de tectable levels. Interestingly, the levels of N-myc and c-jun mRNAs in the cartinoid tumors were elevated 19- and 8-fold, respectively, as c ompared with those found in the control intestine. In contrast, the ma jor histocompatibility complex (MHC) class I mRNA level was not altere d between the tumor and control intestines, suggesting that this uncha nged expression may reflect the loss of tumor metastasis. These findin gs provide the first in vivo evidence that the expression of the Ad12 El region gene induces cartinoid tumors associated with the activation of the nuclear oncogenes N-mye and c-jun.