Research ArticleCancer

The protein kinase p38α destabilizes p63 to limit epidermal stem cell frequency and tumorigenic potential

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Science Signaling  09 Oct 2018:
Vol. 11, Issue 551, eaau0727
DOI: 10.1126/scisignal.aau0727

A p38α-p63 balancing act in skin cancer

Loss of p38α in mice leads to hyperplasia and tumor development in epithelial tissues. Choo et al. analyzed skin tissue and cells from normal donors, patients with premalignant keratosis or squamous cell carcinoma (SCC), and mouse models and found that p38α phosphorylated and consequently induced the degradation of the transcription factor p63, particularly that of its tumor-associated isoform ΔNp63α. Loss of p38α increased p63 abundance in the skin and thereby enhanced the expression of stem cell–associated genes, repressed the expression of a tumor-suppressive metalloprotease, and promoted stem cell outgrowth in the skin. The findings also raise the possibility that p38α inhibitors used to treat other cancers (where p38α is tumor promotive) may cause secondary SCC in patients.


The molecular circuitry directing tissue development and homeostasis is hardwired by genetic programs but may also be subject to fine-tuning or major modification by environmental conditions. It remains unclear whether such malleability is at work—particularly in tissues directly in contact with the environment—and contributes to their optimal maintenance and resilience. The protein kinase p38α is activated by physiological cues that signal tissue damage and neoplastic transformation. Here, we found that p38α phosphorylated and thereby destabilized p63, a transcription factor essential for epidermal development. Through this regulatory mechanism, p38α limited the frequency of keratinocytes with stem cell properties and tumorigenic potential. Correspondingly, epidermal loss of p38α expression or activity promoted or correlated with carcinogenesis in mouse and human skin, respectively. Genetic mouse models revealed a tumorigenic mechanism from p38α loss through p63-mediated suppression of the matrix metalloprotease MMP13. These findings illustrate a previously uncharacterized epidermal tumor–suppressive mechanism in which stress-activated signaling induces the contraction of stem cell–like keratinocyte pools.

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