McEwen Donald G, Peifer Mark
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3280, USA.
Development. 2005 Sep;132(17):3935-46. doi: 10.1242/dev.01949. Epub 2005 Aug 3.
MAPK phosphatases (MKPs) are important negative regulators of MAPKs in vivo, but ascertaining the role of specific MKPs is hindered by functional redundancy in vertebrates. Thus, we characterized MKP function by examining the function of Puckered (Puc), the sole Drosophila Jun N-terminal kinase (JNK)-specific MKP, during embryonic and imaginal disc development. We demonstrate that Puc is a key anti-apoptotic factor that prevents apoptosis in epithelial cells by restraining basal JNK signaling. Furthermore, we demonstrate that JNK signaling plays an important role in gamma-irradiation-induced apoptosis, and examine how JNK signaling fits into the circuitry regulating this process. Radiation upregulates both JNK activity and puc expression in a p53-dependent manner, and apoptosis induced by loss of Puc can be suppressed by p53 inactivation. JNK signaling acts upstream of both Reaper and effector caspases. Finally, we demonstrate that JNK signaling directs normal developmentally regulated apoptotic events. However, if cell death is prevented, JNK activation can trigger tissue overgrowth. Thus, MKPs are key regulators of the delicate balance between proliferation, differentiation and apoptosis during development.
丝裂原活化蛋白激酶磷酸酶（MKPs）是体内丝裂原活化蛋白激酶（MAPKs）的重要负调控因子，但脊椎动物中功能冗余阻碍了确定特定MKPs的作用。因此，我们通过在胚胎和成虫盘发育过程中研究唯一的果蝇c-Jun氨基末端激酶（JNK）特异性MKP——褶皱蛋白（Puc）的功能来表征MKP的功能。我们证明Puc是一种关键的抗凋亡因子，通过抑制基础JNK信号传导来防止上皮细胞凋亡。此外，我们证明JNK信号传导在γ射线诱导的凋亡中起重要作用，并研究JNK信号传导如何融入调节这一过程的信号通路。辐射以p53依赖的方式上调JNK活性和puc表达，并且通过p53失活可以抑制因Puc缺失诱导的凋亡。JNK信号传导在收割者蛋白（Reaper）和效应半胱天冬酶的上游起作用。最后，我们证明JNK信号传导指导正常的发育调控凋亡事件。然而，如果细胞死亡被阻止，JNK激活会触发组织过度生长。因此，MKPs是发育过程中增殖、分化和凋亡之间微妙平衡的关键调节因子。
