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

Oncogene volume 23, pages 91–99 (2004)Cite this article

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.

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Acknowledgements

We specially thank Dr V Bourdeau, L Chatel-Chaix, Dr L DesGroseillers, Dr E Querido and Dr M Soengas for reviewing the manuscript, Dr Karl Munger for useful suggestions, Dr H-J Heidebrecht for the anti-Mcm6 antibody and Drs D Galloway and P Howley for plasmids and useful suggestions. This research was supported by Grant 86239 from the Canadian Institute of Health and Research.

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Author notes

  1. Frédérick A Mallette and Stéphane Goumard: These two authors contributed equally to this work

  2. Gerardo Ferbeyre: Delivery address: Département de Biochimie, Université de Montréal, Pavillon Principal, A-533, 2900 Édouard Montpetit, Montréal, Québec, Canada H3T 1J4

Authors and Affiliations

  1. Département de biochimie, Université de Montréal, Montréal, H3C 3J7, Québec, Canada

    Frédérick A Mallette, Stéphane Goumard, Marie-France Gaumont-Leclerc, Olga Moiseeva & Gerardo Ferbeyre

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  1. Frédérick A Mallette
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Correspondence to Gerardo Ferbeyre.

Supplementary information

Supplementary Figure S1

E7 induces cell death in HDFs. IMR90 cells expressing LXSN, E6, E7, or E6/E7 were infected with a PML-expressing retrovirus or a control vector. Cell death was scored 1 day after selection using Trypan blue staining (TIF 139 kb)

Supplementary Figure S2 and Table SI

Effects of individual expression of E6 and E7 on PML bodies. Cells bearing the control vector LXSN or its derivative containing E6 or E7 were infected with either another control vector or its derivatives expressing PML. PML bodies were visualized by indirect immunofluorescence using the anti-PML antibody PG-M3. Nuclei were counterstained with DAPI (TIF 2306 kb)

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Mallette, F., Goumard, S., Gaumont-Leclerc, MF. et al. Human fibroblasts require the Rb family of tumor suppressors, but not p53, for PML-induced senescence. Oncogene 23, 91–99 (2004). https://doi.org/10.1038/sj.onc.1206886

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