The protein kinase p38? destabilizes p63 to limit epidermal stem cell frequency and tumorigenic potential.

ABSTRACT: 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 p38? is activated by physiological cues that signal tissue damage and neoplastic transformation. Here, we found that p38? phosphorylated and thereby destabilized p63, a transcription factor essential for epidermal development. Through this regulatory mechanism, p38? limited the frequency of keratinocytes with stem cell properties and tumorigenic potential. Correspondingly, epidermal loss of p38? expression or activity promoted or correlated with carcinogenesis in mouse and human skin, respectively. Genetic mouse models revealed a tumorigenic mechanism from p38? 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.

SUBMITTER: Choo MK 

PROVIDER: S-EPMC6207192 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature