Li Gang, Ying Li, Wang Hong, Wei Si-Si, Chen Jie, Chen Yi-He, Xu Wei-Ping, Jie Qi-Qiang, Zhou Qing, Li Yi-Gang, Wei Yi-Dong, Wang Yue-Peng
Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China.
Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Oncotarget. 2016 Apr 5;7(14):17970-85. doi: 10.18632/oncotarget.7602.
Rac1b is a constitutively activated, alternatively spliced form of the small GTPase Rac1. Previous studies showed that Rac1b promotes cell proliferation and inhibits apoptosis. In the present study, we used microarray analysis to detect genes differentially expressed in HEK293T cells and SW480 human colon cancer cells stably overexpressing Rac1b. We found that the pro-proliferation genes JNK2, c-JUN and cyclin-D1 as well as anti-apoptotic AKT2 and MCL1 were all upregulated in both lines. Rac1b promoted cell proliferation and inhibited apoptosis by activating the JNK2/c-JUN/cyclin-D1 and AKT2/MCL1 pathways, respectively. Very low Rac1b levels were detected in the colonic epithelium of wild-type Sprague-Dawley rats. Knockout of the rat Rac1 gene exon-3b or knockdown of endogenous Rac1b in HT29 human colon cancer cells downregulated only the AKT2/MCL1 pathway. Our study revealed that very low levels of endogenous Rac1b inhibit apoptosis, while Rac1b upregulation both promotes cell proliferation and inhibits apoptosis. It is likely the AKT2/MCL1 pathway is more sensitive to Rac1b regulation.
Rac1b是小GTP酶Rac1的一种组成型激活的可变剪接形式。先前的研究表明，Rac1b促进细胞增殖并抑制细胞凋亡。在本研究中，我们使用微阵列分析来检测在稳定过表达Rac1b的HEK293T细胞和SW480人结肠癌细胞中差异表达的基因。我们发现，促增殖基因JNK2、c-JUN和细胞周期蛋白D1以及抗凋亡的AKT2和MCL1在这两种细胞系中均上调。Rac1b分别通过激活JNK2/c-JUN/细胞周期蛋白D1和AKT2/MCL1途径促进细胞增殖并抑制细胞凋亡。在野生型Sprague-Dawley大鼠的结肠上皮中检测到非常低水平的Rac1b。敲除大鼠Rac1基因外显子3b或在HT29人结肠癌细胞中敲低内源性Rac1b仅下调AKT2/MCL1途径。我们的研究表明，极低水平的内源性Rac1b抑制细胞凋亡，而Rac1b的上调既促进细胞增殖又抑制细胞凋亡。AKT2/MCL1途径可能对Rac1b调节更敏感。
