Marinissen Maria Julia, Chiariello Mario, Tanos Tamara, Bernard Ora, Narumiya Shuh, Gutkind J Silvio
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Mol Cell. 2004 Apr 9;14(1):29-41. doi: 10.1016/s1097-2765(04)00153-4.
RhoA regulates the actin cytoskeleton and the expression of genes associated with cell proliferation. This includes c-fos and c-jun, which are members of the AP1 family of transcription factors that play a key role in normal and aberrant cell growth. Whereas RhoA stimulates the c-fos SRE by a recently elucidated mechanism that is dependent on actin treadmilling, how RhoA regulates c-jun is still poorly understood. We found that RhoA stimulates c-jun expression through ROCK, but independently from the ability of ROCK to promote actin polymerization. Instead, we found that ROCK activates JNK, which then phosphorylates c-Jun and ATF2 when bound to the c-jun promoter. Thus, ROCK represents a point of signal divergence downstream from RhoA, as it promotes actin reorganization and the consequent expression from the c-fos SRE, while a parallel pathway connects ROCK to JNK, thereby stimulating c-jun expression. Ultimately, these pathways converge in the nucleus to regulate AP1 activity.
RhoA调节肌动蛋白细胞骨架以及与细胞增殖相关的基因表达。这包括c-fos和c-jun，它们是AP1转录因子家族的成员，在正常和异常细胞生长中起关键作用。虽然RhoA通过一种最近阐明的依赖于肌动蛋白踏车行为的机制刺激c-fos SRE，但RhoA如何调节c-jun仍知之甚少。我们发现RhoA通过ROCK刺激c-jun表达，但独立于ROCK促进肌动蛋白聚合的能力。相反，我们发现ROCK激活JNK，当JNK与c-jun启动子结合时，它会磷酸化c-Jun和ATF2。因此，ROCK代表了RhoA下游信号分歧的一个点，因为它促进肌动蛋白重组以及随后c-fos SRE的表达，而一条平行途径将ROCK与JNK连接起来，从而刺激c-jun表达。最终，这些途径在细胞核中汇聚以调节AP1活性。
