Abstract
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.
Highlights
The small GTPase, Rac1, controls numerous cellular activities by cycling between an active GTP-bound form and an inactive GDP-bound form [1,2,3]
Up to 30 cycles, Rac1 transcript differences narrowed between LV-puro and LV-Rac1 cells due to saturation, and a faint endogenous Rac1 transcript band was observed in Rac1b cells
We found that JNK2 (2.34-fold) and c-JUN (2.16fold), both part of the mitogen-activated protein kinase (MAPK) pathway that works to promote cell cycle progression, were upregulated, but JNK1 and JNK3 were not included in the 505 differentially expressed genes (DEGs) (Table S1)
Summary
The small GTPase, Rac, controls numerous cellular activities by cycling between an active GTP-bound form and an inactive GDP-bound form [1,2,3]. These processes are tightly regulated by three groups of proteins: guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDIs) [4, 5]. Rac stimulates other transcription factors, including NF-kB and serum response factor (SRF) [9,10,11,12,13] Activation of these transcription factors leads to cyclin-D1 up-regulation, which promotes G1/S-phase progression
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