Effects of human cytomegalovirus major immediate-early proteins in controlling the cell cycle and inhibiting apoptosis: Studies with ts13 cells

The major immediate-early (MIE) gene of human cytomegalovirus (HCMV) encode s several MIE proteins (MIEPs) produced as a result of alternative splicing and polyadenylation of the primary transcript. Previously we demonstrated that the HCMV MIEPs expressed from the entire MIE gene could rescue the tem perature-sensitive (ts) transcriptional defect in the ts13 cell line. This defect is caused by a ts mutation in TAF(II)250, the 250-kDa TATA binding p rotein-associated factor (TAF). These and other data suggested that the MIE Ps perform a TAF-like function in complex with the basal transcription fact or TFIID. In addition to the transcriptional defect, the ts mutation in ts1 3 cells results in a defect in cell cycle progression which ultimately lead s to apoptosis. Since all of these defects can be rescued by wild-type TAF( II)250, we asked whether the MIEPs could rescue the cell cycle defect and/o r affect the progression to apoptosis. We have found that the MIEPs, expres sed from the entire MIE gene, do not rescue the cell cycle block in ts13 ce lls grown at the nonpermissive temperature. However, despite the maintenanc e of the cell cycle block, the ts13 cells which express the MIEPs are resis tant to apoptosis. MIEP mutants, which have previously been shown to be def ective in rescuing the ts transcriptional defect, maintained the ability to inhibit apoptosis. Hence, the MIEP functions which affect transcription ap pear to be separable from the functions which inhibit apoptosis. We discuss these data in the light of the HCMV life cycle and the possibility that th e MIEPs promote cellular transformation by a "hit-and-run" mechanism.