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.

指导组织发育和体内平衡的分子电路是通过遗传程序进行硬连线的，但也可能会受到环境条件的微调或重大修改。尚不清楚这种延展性是否起作用，特别是在直接与环境接触的组织中是否起作用，并有助于它们的最佳维护和弹性。蛋白激酶p38α被信号提示组织损伤和赘生性转化的生理信号激活。在这里，我们发现p38α磷酸化，从而使p63（表皮发育必不可少的转录因子）不稳定。通过这种调节机制，p38α限制了具有干细胞特性和致癌潜力的角质形成细胞的频率。相应地，p38α表达或活性的表皮丧失分别促进了小鼠和人类皮肤的癌变或与之相关。遗传小鼠模型揭示了从p38α丢失到p63介导的基质金属蛋白酶MMP13抑制的致瘤机理。这些发现说明了以前未知的表皮肿瘤抑制机制，其中应力激活的信号传导诱导干细胞样角质形成细胞池的收缩。