Abstract
It is well established that nuclear factor κB (NF‐κB) acts as one of the most important transcription factors for tumor initiation and progression, as it both protects cells from apoptotic/necrotic signals and accelerates angiogenesis and tumor metastasis, which is mediated via the expression of target genes. However, it has not yet been clarified how oncogenic signals accelerate the activation of NF‐κB. In the current study, we utilized untransformed NIH‐3T3 cells stably harboring a κB‐driven luciferase gene to show that an oncogenic mutant of Ras GTPase augmented TNFα‐induced NF‐κB activation. Notably, enforced expression of cyclin‐dependent kinase inhibitors, such as p27Kip1 and p21Cip1, effectively canceled the accelerated activation of NF‐κB, suggesting that oncogenic Ras‐induced cell cycle progression is essential for the hyperactivation of NF‐κB. Furthermore, we found that Ras (G12V) augmented the transcriptional activation of NF‐κB, and this activation required the p38 MAP kinase. We observed that a downstream kinase of p38 MAP kinase, MSK1, was activated by Ras (G12V) and catalyzed the phosphorylation of p65/RelA at Ser‐276, which is critical for its transcriptional activation. Significantly, phosphorylation of the p65/RelA subunit at Ser‐276 was elevated in patient samples of colorectal cancer harboring oncogenic mutations of the K‐Ras gene, and the expression levels of NF‐κB target genes were drastically enhanced in several cancer tissues. These observations strongly suggest that oncogenic signal‐induced acceleration of NF‐κB activation is caused by activation of the p38 MAP kinase–MSK1 signaling axis and by cell cycle progression in cancer cells.
Highlights
Nuclear factor jB (NF-jB) includes a family of transcription factors, which induce the expression of a number of target genes related to anti-inflammation, development, and the apoptosis-related responses (Baud and Karin, 2009; Ghosh and Hayden, 2008)
We found that the enforced expression of B-Raf (V600E) strongly enhanced the tumor necrosis factor a (TNFa)-induced activation of nuclear factor jB (NF-jB) (Fig. 1E), whereas myristoylated Akt (myr-Akt) only exhibited a slight enhancement of NF-jB activation
To clarify the functional involvement of cell cycle progression induced by oncogenic Ras in the hyperactivation of NF-jB, we investigated the effects of cyclin-dependent kinase (CDK) inhibitors on the oncogenic activation of NF-jB in Ras mutant-provoked transformed cells
Summary
Nuclear factor jB (NF-jB) includes a family of transcription factors, which induce the expression of a number of target genes related to anti-inflammation, development, and the apoptosis-related responses (Baud and Karin, 2009; Ghosh and Hayden, 2008). It is well understood that p50 and p52 are produced by proteolysis of their precursor proteins, NF-jB1 p105 and NF-jB2 p100, respectively These five NF-jB family members possess a Rel homology domain (RHD) contributing to homo- and heterodimerization, nuclear translocation, and interaction with inhibitor proteins such as IjB family (Baldwin, 1996; Ghosh and Karin, 2002). It was reported that NF-jB contributes to tumor progression by accelerating the expression of diverse target genes, which contribute to cell proliferation, angiogenesis, and metastasis. These point mutations cause constitutive activation of Ras proteins by loss of their GTPase activity, and the activation of downstream of Ras proteins is drastically augmented (Bos, 1989; Karnoub and Weinberg, 2008) It is still unclear how these signaling molecules contribute to cellular transformation and tumor progression. We clarified part of the molecular mechanism by which oncogenic Ras mutant-induced signals accelerate the activation of NF-jB
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