| First Author | Choo MK | Year | 2018 |
| Journal | Sci Signal | Volume | 11 |
| Issue | 551 | PubMed ID | 30301786 |
| Mgi Jnum | J:281868 | Mgi Id | MGI:6380886 |
| Doi | 10.1126/scisignal.aau0727 | Citation | Choo MK, et al. (2018) The protein kinase p38alpha destabilizes p63 to limit epidermal stem cell frequency and tumorigenic potential. Sci Signal 11(551) |
| abstractText | 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 p38alpha is activated by physiological cues that signal tissue damage and neoplastic transformation. Here, we found that p38alpha phosphorylated and thereby destabilized p63, a transcription factor essential for epidermal development. Through this regulatory mechanism, p38alpha limited the frequency of keratinocytes with stem cell properties and tumorigenic potential. Correspondingly, epidermal loss of p38alpha expression or activity promoted or correlated with carcinogenesis in mouse and human skin, respectively. Genetic mouse models revealed a tumorigenic mechanism from p38alpha 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. |
