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Studies of Cervical Carcinoma and Senescence

Figure 6. Repression of HPV18 E6/E7 transcription and activation of p53 by expression of E2 transcriptional repressor. Top panel shows HPV 18 E6/E7 northern blot, bottom panels show p53 western blot, at various times after mock treatment of HeLa cells or infection with a viral vector that expresses E2. Adapted from Goodwin et al., PNAS 97: 12513-12518 (2000).

The laboratory is investigating the role of the human papillomavirus E6 and E7 proteins in cervical cancer and oropharyngeal cancer, with particular attention to their ability to inhibit cellular senescence. We showed that expression of the bovine papillomavirus E2 transcription factor represses expression of the E6 and E7 genes from the integrated HPV genomes in human cervical cancer cells, resulting in transient activation of the endogenous p53 and retinoblastoma tumor suppressor pathways and dramatic growth inhibition (Fig. 6).

Figure 7. Induction of senescence by repression of E6 and E7. HeLa cervical cancer wells were left uninfected or infected with a virus expressing the BPV E2 protein to repress HPV18 E6/E7 expression. Uninfected cells proliferate and form dense colonies, but senescent cells induced by HPV repression cease proliferation, flatten and stain blue for senescence-associated ß galactosidase activity. Adapted from DeFilippis et al., J. Virol. 77: 1551-1563 (2003).

These results demonstrated that continued expression of the HPV oncogenes is required to maintain the proliferative state of these cancer cells and imply that manipulations that inhibit the activity of the viral oncoproteins and activate cellular tumor suppressor pathways may be an approach to treat cancer. The growth-arrested cells do not die but rather enter an irreversible non-replicating state that resembles replicative senescence, which normally blocks the unlimited poliferation of cells (Fig. 7). Further analysis showed that Rb activation mobilized a novel microRNA regulatory circuit that resulted in repression of the B-Myb oncogene, which contributes to senescence. In contrast, the reversible growth-arrested state of quiescence induces a novel miRNA biogenesis pathway that is independent of the canonical transport protein, exportin-5.

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