p53 promotes adenoviral replication and increases late viral gene expression

Abstract

The tumor suppressor protein, p53, plays a critical role in viro-oncology. However, the role of p53 in adenoviral replication is still poorly understood. In this paper, we have explored further the effect of p53 on adenoviral replicative lysis. Using well-characterized cells expressing a functional p53 (A549, K1neo, RKO) and isogenic derivatives that do not (K1scx, RKOp53.13), we show that virus replication, late virus protein expression and both wtAd5 and ONYX-015 virus-induced cell death are impaired in cells deficient in functional p53. Conversely, by transfecting p53 into these and other cells (IIICF/c, HeLa), we increase late virus protein expression and virus yield. We also show, using reporter assays in IIICF/c, HeLa and K1scx cells, that p53 can cooperate with E1a to enhance transcription from the major late promoter of the virus. Late viral protein production is enhanced by exogenous p53. Taken together, our data suggest that functional p53 can promote the adenovirus (Ad) lytic cycle. These results have implications for the use of Ad mutants that are defective in p53 degradation, such as ONYX-015, as agents for the treatment of cancers.

Association of MutantTP53with Alternative Lengthening of Telomeres and Favorable Prognosis in Glioma

“…Although SIFT results showed all mutations apart from R273H were deleterious, the R273H mutation has been reported to have defective activity toward promoters of various genes, including BAX, MDM2, and WAF1 (15). We have also found that the R273H mutation fails to enhance activity of adenoviral major late promoter, the principal promoter regulating expression of late virus protein in the presence of E1A (16). The average age of patients with mutant TP53 was significantly younger at diagnosis than those with wild-type (WT) TP53 (49.1 F 3.5 and 59.4 F 1.4 years, respectively; P = 0.0102), which agrees with Louis et al (17).…”

PAX8 Regulates Telomerase Reverse Transcriptase and Telomerase RNA Component in Glioma

“…Cells were also transfected with either pCMV5.PAX8, pCMVPAX2b, pCMVPAX2c, or control pcDNA3 plasmids. Preparation of cell lysates and measurement of luciferase activity (Promega) have been previously described (26). Assays were performed in duplicate and repeated at least twice.…”

E1B55K-Deleted Adenovirus (ONYX-015) Overrides G1/S and G2/M Checkpoints and Causes Mitotic Catastrophe and Endoreduplication in p53-Proficient Normal Cells

“…20,21,23 Studies by Braithwaite and coworkers have also proposed the hypothesis that p53 is actually needed by Ad to exert a cytopathic effect. 24,25 Another ambiguous point concerning ONYX-015 biology relates to the original idea linking the activation of the G 1 /S checkpoint to the abortion of the viral cycle in wt cells. As a matter of fact, the G 1 /S checkpoint is linked to the activity of pRb, 26,27 which is expected to be inactivated by E1A also in ONYX-015-infected cells.…”