Human fibroblasts require the Rb family of tumor suppressors, but not p53, for PML-induced senescence.

Abstract

Cellular senescence is a permanent cell cycle arrest that can be triggered by a variety of stresses including short telomeres and activated oncogenes. Promyelocytic leukemia protein (PML) is a central component of the senescence response, and is able to trigger the process when overexpressed in human diploid fibroblasts (HDFs). Senescence induced by PML in HDFs is characterized by a modest increase in p53 levels and activity, the accumulation of hypophosphorylated Rb and a reduced expression of E2F-dependent genes. To dissect the p53 and Rb family requirements for PML-induced senescence, we used the oncoproteins E6 and E7 from human papillomavirus type 16. We found that the coexpression of E6 and E7 inhibited the growth arrest and senescence induced by PML. In addition, these viral oncoproteins blocked the formation of PML bodies and excluded both p53 and Rb from PML bodies. Expression of dominant-negative p53 alone failed to block PML-induced senescence and expression of E6 only delayed the process. On the other hand, expression of E7 was sufficient to block PML-induced senescence, while an E7 mutant unable to bind Rb did not. Together, these data indicate that PML-induced senescence engages the Rb tumor-suppressor pathway predominantly.