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Cyclin E drives human keratinocyte growth into differentiation

Oncogene volume 31, pages 5180–5192 (2012)Cite this article

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Abstract

Human epidermis is continuously exposed to environmental mutagenic hazard and is the most frequent target of human cancer. How the epidermis coordinates proliferation with differentiation to maintain homeostasis, even in hyperproliferative conditions, is unclear. For instance, overactivation of the proto-oncogene MYC in keratinocytes stimulates differentiation. Here we explore the cell cycle regulation as proliferating human keratinocytes commit to terminal differentiation upon loss of anchorage or overactivation of MYC. The S-phase of the cell cycle is deregulated as mitotic regulators are inhibited in the onset of differentiation. Experimental inhibition of mitotic kinase cdk1 or kinases of the mitosis spindle checkpoint Aurora B or Polo-like Kinase, triggered keratinocyte terminal differentiation. Furthermore, hyperactivation of the cell cycle by overexpressing the DNA replication regulator Cyclin E induced mitosis failure and differentiation. Inhibition of Cyclin E by shRNAs attenuated the induction of differentiation by MYC. In addition, we present evidence that Cyclin E induces DNA damage and the p53 pathway. The results provide novel clues for the mechanisms committing proliferative keratinocytes to differentiate, with implications for tissue homeostasis maintenance, HPV amplification and tumorigenesis.

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Acknowledgements

We are especially grateful to Jean-Claude Rossi and Javier León for their strong support. We thank Bruno Amati, Pierre Roux and Jonathon Pines for providing DNA constructs, J. León for reagents, Anne Blangy, Vjeko Dulic, Véronique Baldin and Thierry Lorca for technical advice, Daniel Fisher for helpful suggestions, Kathy Brooks and María Aramburu for technical support at flow cytometry, J. Leon and Philippe Pasero for critical reading of the manuscript, and Anna Solinís and Diana Solinís for reviewing the English writing. Human skin biopsies were provided with consent by St Jean and Hôpital La Peronye (Montpellier, France) and by the Chirurgical Paediatric Service of Hospital Marqués de Valdecilla (EdD; HMDV, Santander, Spain). MC was a recipient of a predoctoral fellowship from ARC (France). AG belongs to the INSERM (France) and the FMDV-IFIMAV (Spain) and was financially supported by the INSERM and the ISCIII (Spain). AF and LC were employed by FMDV-IFIMAV and supported by the ISCIII, MR was recipient of a postdoctoral contract by the FMDV-IFIMAV. This work was funded by ARC (AG; France), La Ligue contre le cancer (JMB; France), and Instituto de Salud Carlos III (AG; ISCIII-Programa Regiones Emergentes and Fondo de Investigaciones Sanitarias PI080890; Spain).

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Authors and Affiliations

  1. Cell Cycle, Stem Cell Fate and Cancer Laboratory. Institute for Training and Research of the Fundación Marqués de Valdecilla (IFIMAV-FMDV), Santander, Spain

    A Freije, L Ceballos, M Rosa & A Gandarillas

  2. Molecular Biology Department of Universidad de Cantabria (UC), Santander, Spain

    A Freije, L Ceballos, M Rosa & A Gandarillas

  3. Institut de Génètique Moléculaire de Montpellier (CNRS/UMPII), Montpellier, France

    M Coisy, L Barnes, J M Blanchard & A Gandarillas

  4. Servicio de Cirugía Pediátrica, Hospital Universitario Marqués de Valdecilla (HUMV), Santander, Spain

    E De Diego

  5. Laboratoire de Dermatologie Moléculaire, UPRES EA 3754, Institut Universitaire de Recherche Clinique, Inserm ADR Languedoc-Roussillon, Montpellier, France

    A Gandarillas

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  1. A Freije
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  2. L Ceballos
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  3. M Coisy
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Correspondence to A Gandarillas.

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Freije, A., Ceballos, L., Coisy, M. et al. Cyclin E drives human keratinocyte growth into differentiation. Oncogene 31, 5180–5192 (2012). https://doi.org/10.1038/onc.2012.22

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