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p21CIP1 controls the squamous differentiation response to replication stress

Oncogene volume 40, pages 152–162 (2021)Cite this article

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Abstract

The control of cell fate is critical to homeostasis and cancer. Cell cycle cdk inhibitor p21CIP1 has a central and paradoxical role in the regulatory crossroads leading to senescence, apoptosis, or differentiation. p21 is an essential target of tumor suppressor p53, but it also is regulated independently. In squamous self-renewal epithelia continuously exposed to mutagenesis, p21 controls cell fate by mechanisms still intriguing. We previously identified a novel epidermoid DNA damage-differentiation response. We here show that p21 intervenes in the mitosis block that is required for the squamous differentiation response to cell cycle deregulation and replication stress. The inactivation of endogenous p21 in human primary keratinocytes alleviated the differentiation response to oncogenic loss of p53 or overexpression of the DNA replication major regulator Cyclin E. The bypass of p21-induced mitotic block involving upregulation of Cyclin B allowed DNA damaged cells to escape differentiation and continue to proliferate. In addition, loss of p21 drove keratinocytes from differentiation to apoptosis upon moderate UV irradiation. The results show that p21 is required to drive keratinocytes towards differentiation in response to genomic stress and shed light into its dual and paradoxical role in carcinogenesis.

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Fig. 1: p21 knockdown results in loss of squamous differentiation.
Fig. 2: p21 is required for the antiproliferative differentiation response to inactivation of p53.
Fig. 3: Loss of p21 drives p53 knockdown cells to proliferate with high levels of DNA damage.
Fig. 4: p21 mediates the squamous differentiation response to deregulation of Cyclin E.
Fig. 5: Loss of p21 allows keratinocytes to proliferate with high levels of Cyclin E-induced replication stress.
Fig. 6: Loss of p21 drives UV-induced squamous differentiation into apoptosis.
Fig. 7: Model for p21 dependent and independent triggers of squamous terminal squamous differentiation.

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Acknowledgements

This work was funded by Instituto de Salud Carlos III/FEDER (AG; Spain), grants PI14/00900 and PI17/01307. IdP was in part supported by lab resources, by ISCIII-FEDER PI1400900 and by a scholarship from IFC (Industrial Farmacéutica Cantabria, currently Cantabria Labs; Spain). JG is recipient of a predoctoral scholarship from Asociación Española Contra el Cáncer (AECC; Spain), PRDCA19003GALA. We thank Jeannette G. Cook for the doxycycline-inducible Cyclin E construct.

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  1. These authors contributed equally: Isabel de Pedro, Jesús Galán-Vidal

Authors and Affiliations

  1. Cell Cycle, Stem Cell Fate and Cancer Laboratory, Institute for Research Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain

    Isabel de Pedro, Jesús Galán-Vidal, Ana Freije, Ernesto de Diego & Alberto Gandarillas

  2. Paediatric Surgery, Hospital Universitario Marqués de Valdecilla, 39008, Santander, Spain

    Ernesto de Diego

  3. INSERM, Languedoc-Roussillon, 34394, Montpellier, France

    Alberto Gandarillas

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Correspondence to Alberto Gandarillas.

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de Pedro, I., Galán-Vidal, J., Freije, A. et al. p21CIP1 controls the squamous differentiation response to replication stress. Oncogene 40, 152–162 (2021). https://doi.org/10.1038/s41388-020-01520-8

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