KMID : 0613820220320110833
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Journal of Life Science 2022 Volume.32 No. 11 p.833 ~ p.840
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CLK3 is a Novel Negative Regulator of NF-¥êB Signaling
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Jeon Byeol-Eun
Kwo Chan-Seong Lee Ji-Eun Woo Ye-Lin Kim Sang-Woo
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Abstract
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Chronic inflammation has been shown to be closely associated with tumor development and progression. Nuclear factor kappa B (NF-¥êB) is composed of a family of five transcription factors. NF-¥êB signaling plays a crucial role in the inflammatory response and is often found to be dysregulated in various types of cancer, making it an attractive target in cancer therapeutics. In this study, CDC-like kinase 3 (CLK3) was identified as a novel kinase that regulates the NF-¥êB signaling pathway. Our data demonstrate that CLK3 inhibits the canonical and non-canonical NF-¥êB pathways. Luciferase
assays following the transient or stable expression of CLK3 indicated that this kinase inhibited NF-¥êB activation mediated by Tumor necrosis factor-alpha (TNF¥á) and Phorbol 12-myristate 13-acetate (PMA), which are known to activate NF-¥êB signaling via the canonical pathway. Consistent with data on the ectopic expression of CLK3, CLK3 knockdown using shRNA constructs increased NF-¥êB activity 1.5-fold upon stimulation with TNF¥á in HEK293 cells compared with the control cells. Additionally, overexpression of CLK3 suppressed the activation of this signaling pathway induced by NF-¥êB-inducing kinase (NIK) or CD40, which are well-established activators of the non-canonical pathway. To further examine the negative impact of CLK3 on NF-¥êB signaling, we performed Western blotting following the TNF¥á treatment to directly identify the molecular components of the NF-¥êB pathway that are affected by this kinase. Our results revealed that CLK3 mitigated the phosphor- ylation/activation of transforming growth factor-¥â-activated kinase 1 (TAK1), inhibitor of NF-¥êB kinase alpha/beta (IKK¥á/¥â), NF-¥êB p65 (RelA), NF-¥êB inhibitor alpha (I¥êB¥á), and Extracellular signal-regulated kinase 1/2-Mitogen-activated protein kinase (ERK1/2-MAPK), suggesting that CLK3 inhibits both the NF-¥êB and MAPK signaling activated by TNF¥á exposure. Further studies are required to elucidate the mechanism by which CLK3 inhibits the canonical and non-canonical NF-¥êB pathways. Collectively, these findings reveal CLK3 as a novel negative regulator of NF-¥êB signaling.
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KEYWORD
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Cancer, CLK3, inflammation, MAPK, NF-¥êB
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