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Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2

Nature Cell Biology volume 9, pages 331338 (2007) | Download Citation

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Abstract

The p300–CBP-associated factor (PCAF) is a histone acetyltransferase (HAT) involved in the reversible acetylation of various transcriptional regulators1, including the tumour suppressor p53. It is implicated in many cellular processes, such as transcription, differentiation, proliferation and apoptosis. We observed that knockdown of PCAF expression in HeLa or U2OS cell lines induces stabilization of the oncoprotein Hdm2, a RING finger E3 ligase primarily known for its role in controlling p53 stability2,3. To investigate the molecular basis of this effect, we examined whether PCAF is involved in Hdm2 ubiquitination. Here, we show that PCAF, in addition to its acetyltransferase activity, possesses an intrinsic ubiquitination activity that is critical for controlling Hdm2 expression levels, and thus p53 functions. Our data highlight a regulatory crosstalk between PCAF and Hdm2 activities, which is likely to have a central role in the subtle control of p53 activity after DNA damage.

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Acknowledgements

We thank V. Ogryzko for Flag–PCAF C-terminal deletion mutants, V. Favaudon for NCS, M. Oren for HA–Hdm2 expression vector, Y. Boublik (Recombinant Protein Platform, CRBM–CNRS) for production of baculovirus-expressed proteins, G. Lledo for enzyme production. We also thank our colleagues for their help, suggestions and criticisms, particularly the members of our groups and V. Gire, M. Piechaczyk and C. Sardet. This work was supported by grants from the Human Frontier Science Program (Young Investigator Program) to M.B., Action Concertée Incitative (ACI; M.B.) and ACI Biologie Cellulaire, Moléculaire et Structurale (O. Coux) from the French Ministère de la Recherche, Sidaction (M.B. and O. Coux), Association pour la Recherche sur le Cancer (ARC; O. Coux), and European contracts n°QLG1-CT-2001-02026 (O. Coux) and 012182 (M.B.). L.L. was supported by fellowships from Sidaction and ANRS (Agence Nationale de Recherches sur le Sida), C.C.B. by the Human Frontier Science Program, and O. Cuvier by a fellowship from the Fondation pour la Recherche Médicale.

Author information

Author notes

    • Laëtitia K. Linares
    •  & Rosemary Kiernan

    These authors contributed equally to this work.

Affiliations

  1. Centre de Recherches de Biochimie Macromoléculaire, CNRS-UMII UMR5237, Montpellier, France.

    • Laëtitia K. Linares
    •  & Olivier Coux
  2. Laboratoire de Virologie Moléculaire, Institut de Génétique Humaine, CNRS UPR1142 Montpellier, France.

    • Rosemary Kiernan
    • , Robinson Triboulet
    • , Christine Chable-Bessia
    • , Daniel Latreille
    •  & Monsef Benkirane
  3. Laboratoire de Dynamique du Génome et Développement, Institut de Génétique Humaine, CNRS UPR1142 Montpellier, France.

    • Olivier Cuvier
  4. Institut de Génétique Moléculaire de Montpellier, CNRS-UMII UMR5535, Montpellier, France

    • Matthieu Lacroix
    •  & Laurent Le Cam

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The authors declare no competing financial interests.

Corresponding authors

Correspondence to Olivier Coux or Monsef Benkirane.

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DOI

https://doi.org/10.1038/ncb1545

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