LOCALIZATION AND STRUCTURE OF V-MOS IN TRANSFORMED MOUSE FIBROBLASTS REVERTED BY LONG-TERM INTERFERON TREATMENT TO NONMALIGNANCY

We have reported previously that Moloney virus-transformed cells, when treated for over 200 passages in the presence of low concentrations o f mouse interferon-alpha/beta, can be reverted to a stable nonmalignan t status. The cells recover full contact inhibition and are unable to raise tumors when grafted in nude mice. In the present report, we show that whether reverted or malignant, these cells contain deleted v-mos oncogenes, which have lost 392 nucleotides. The truncated oncogenes c ontain a reduced and modified open reading frame but are able, however , to induce tumors when transfected in mouse 3T3 cells. As there is no difference either in the location or in the structure of this modifie d v-mos, whether yielded by reverted or malignant cells, we postulate that both cell lines derive from the same population and this modifica tion does not play any role in the reversion process obtained through prolonged IFN-dependent selection. We suggest that reversion could be an epigenetic phenomenon, involving the constitutive synthesis of IFN- beta only in the reverted and not in the malignant cells. The continue d persistence of such noncancerous cells could result at least partly from a balance involving the expression of v-mos, IFN-beta, and an IFN antagonist, sarcolectin. These reverted cells can undergo an unlimite d number of passages, but they must be trypsinized before day 5 in con fluent cultures. Thereafter, the cells stop dividing, cannot prolifera te anymore, progressively show signs of apoptosis, and die.