Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
Cell Cycle. 2012 Mar 15;11(6):1090-6. doi: 10.4161/cc.11.6.19453.
The transcriptional co-activator YAP is an evolutionarily conserved regulator of organ size and progenitor cell proliferation. YAP is overexpressed at high frequency in many common human cancers and can directly drive cancer development in mouse models. YAP abundance and nuclear localization are negatively regulated by the Hippo kinase cascade, which, in epithelia, is activated by physiological cell-cell contact. Recent work in intestinal epithelium has established that YAP is constitutively inhibited by the Hippo pathway and entirely dispensable for normal development and homeostasis. YAP serves only in a standby capacity; should cell-cell contact be abrogated, as after intestinal damage, the loss of Hippo input permits increased YAP abundance and nuclear residence. In turn, YAP cooperates with β-catenin to transactivate genes that promote stem cell expansion for epithelial repair. This interplay between overexpressed YAP and β-catenin also drives proliferation of colon cancer cells. The dispensability of YAP in normal intestine makes YAP's expression or outputs attractive targets for cancer therapy.
转录共激活因子 YAP 是一种进化上保守的器官大小和祖细胞增殖的调节剂。YAP 在许多常见的人类癌症中高频过表达，并可直接在小鼠模型中驱动癌症发生。YAP 的丰度和核定位受 Hippo 激酶级联的负调控，在细胞上皮中，该级联通过生理细胞-细胞接触被激活。最近在肠道上皮中的研究工作已经确定，YAP 被 Hippo 通路持续抑制，对于正常发育和稳态完全是可有可无的。YAP 只是处于备用状态；一旦细胞-细胞接触被消除，例如在肠道损伤后，Hippo 输入的丢失允许 YAP 丰度增加和核定位。反过来，YAP 与β-catenin 合作，反式激活促进上皮修复的干细胞扩增基因。过表达的 YAP 和 β-catenin 之间的这种相互作用也驱动结肠癌细胞的增殖。YAP 在正常肠道中的可有可无性使得 YAP 的表达或输出成为癌症治疗的有吸引力的靶标。
