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Differing tumor-suppressor functions of Arf and p53 in murine basal cell carcinoma initiation and progression

Oncogene volume 36, pages 3772–3780 (2017)Cite this article

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Abstract

Human basal cell carcinomas (BCCs) very frequently carry p53 mutations, and p53 loss markedly accelerates murine BCC carcinogenesis. We report here our studies of the mechanism by which p53 is activated to suppress BCC carcinogenesis. We find that aberrant hedgehog signaling in microscopic BCCs activates p53 in part via Arf (that is, the oncogene-induced stress pathway) but not via the DNA damage response pathway. However, Arf loss and p53 loss produce differing outcomes—loss of p53 promotes both tumor initiation and progression; loss of Arf promotes tumor progression but not initiation. Intriguingly, increased expression of Arf in tumor stromal cells, as in tumor keratinocytes themselves, contributes to suppression of BCC carcinogenesis.

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Acknowledgements

We thank Peter Lamb at Exelixis for providing XL-139 and Charles Sherr for both providing mice carrying the Arf-GFP allele and for wise, ongoing counsel. This work was supported by NIH grant # R01CA163611 (PI: EHE), the American Skin Association (PI: GYW) and the Skin Cancer Foundation (PI: GYW).

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  1. Children’s Hospital Oakland Research Institute, Oakland, CA, USA

    G Y Wang, C N Wood, J A Dolorito, E Libove & E H Epstein Jr

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  1. G Y Wang
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Correspondence to G Y Wang or E H Epstein Jr.

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EHE is a founder and shareholder in PellePharm. The remaining authors declare no conflict of interest.

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Wang, G., Wood, C., Dolorito, J. et al. Differing tumor-suppressor functions of Arf and p53 in murine basal cell carcinoma initiation and progression. Oncogene 36, 3772–3780 (2017). https://doi.org/10.1038/onc.2017.12

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