The protein kinase p38α destabilizes p63 to limit epidermal stem cell frequency and tumorigenic potential.
The protein kinase p38α destabilizes p63 to limit epidermal stem cell frequency and tumorigenic potential.
复制标题
DOI：
10.1126/scisignal.aau0727
复制
发表时间：
2018-10-09
影响因子：
7.3
通讯作者：
Park JM
中科院分区：
文献类型：
--
作者：
Choo MK;Kraft S;Missero C;Park JM
指导组织发育和体内平衡的分子电路由遗传程序硬连线，但也可能受到环境条件的微调或重大修改。目前还不清楚这种延展性是否真的在起作用特别是在直接与环境接触的组织中并有助于它们的最佳维持和恢复。蛋白激酶p38α被信号组织损伤和肿瘤转化的生理信号激活。在这里，我们发现p38α磷酸化，从而使p63不稳定，p63是表皮发育所必需的转录因子。通过这种调节机制，p38α限制了具有干细胞特性和致瘤潜力的角质形成细胞的频率。相应地，表皮p38α表达或活性的丧失分别促进小鼠和人皮肤的癌变并与癌变相关。这些发现阐明了一种新的表皮肿瘤抑制机制，其中应激激活的信号传导诱导干细胞样角质形成细胞池的收缩。
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 indeed 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 and correlated with carcinogenesis in mouse and human skin, respectively. These findings illustrate a novel epidermal tumor-suppressive mechanism in which stress-activated signaling induces the contraction of stem cell-like keratinocyte pools.
登录
查看更多内容
影响因子：
30.8
作者：
Kiemeney LA;Thorlacius S;Sulem P;Geller F;Aben KK;Stacey SN;Gudmundsson J;Jakobsdottir M;Bergthorsson JT;Sigurdsson A;Blondal T;Witjes JA;Vermeulen SH;Hulsbergen-van de Kaa CA;Swinkels DW;Ploeg M;Cornel EB;Vergunst H;Thorgeirsson TE;Gudbjartsson D;Gudjonsson SA;Thorleifsson G;Kristinsson KT;Mouy M;Snorradottir S;Placidi D;Campagna M;Arici C;Koppova K;Gurzau E;Rudnai P;Kellen E;Polidoro S;Guarrera S;Sacerdote C;Sanchez M;Saez B;Valdivia G;Ryk C;de Verdier P;Lindblom A;Golka K;Bishop DT;Knowles MA;Nikulasson S;Petursdottir V;Jonsson E;Geirsson G;Kristjansson B;Mayordomo JI;Steineck G;Porru S;Buntinx F;Zeegers MP;Fletcher T;Kumar R;Matullo G;Vineis P;Kiltie AE;Gulcher JR;Thorsteinsdottir U;Kong A;Rafnar T;Stefansson K
通讯作者：
Stefansson K
影响因子：
56.9
作者：
HAN, J;LEE, JD;ULEVITCH, RJ
通讯作者：
ULEVITCH, RJ
影响因子：
10.5
作者：
Coussens, LM;Raymond, WW;Hanahan, D
通讯作者：
Hanahan, D
DOI：
10.1126/science.1242281
发表时间：
2014-06-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Blanpain C;Fuchs E
通讯作者：
Fuchs E
影响因子：
30.8
作者：
Hui, Lijian;Bakiri, Latifa;Wagner, Erwin F.
通讯作者：
Wagner, Erwin F.