Rac1b enhances cell survival through activation of the JNK2/c-JUN/Cyclin-D1 and AKT2/MCL1 pathways

Li, Gang; Li, Ying; Wang, Hong; Wei, Sisi; Chen, Jie; Chen, Yi-He; Xu, Wengui; Jie, Qiqiang; Zhou, Qing; Li, Yi‐Gang; Wei, Yidong; Wang, Yuepeng

doi:10.18632/oncotarget.7602

Cited by 23 publications

(21 citation statements)

References 60 publications

(106 reference statements)

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“…Our data support these findings, as Rac1b and also Rac1 increased the proliferation of H23 NSCLA cells, which exhibit heterozygously activated K-Ras [ (Zondag et al, 2000) and K. Giehl unpublished results]. Along the same line of evidence, Li et al demonstrated that Rac1b is specifically able to activate JNK2/c-jun together with AKT2, thereby improving cell viability and cell cycle progression of colon cancer cells (Li et al, 2016). However, Rac1b did not induce EMT or enhanced cell invasion in our model.…”

Section: Discussionsupporting

confidence: 86%

“…The effect of both Rac1 isoforms on proliferation of H23 cells correlates with the finding that both Rac1 forms increased the activation of different kinases involved in proliferation control such as p38, AKT and GSK3β in the analyzed lung adenocarcinoma cells. A recent publication by Li et al supports the role of Rac1b in proliferation and inhibition of apoptosis by the activation of JNK2 (Li et al, 2016). However, earlier studies emphasize that Rac1b did not activate p21 protein kinase nor its downstream protein kinase JNK (Matos et al, 2003;Esufali et al, 2007).…”

Section: Discussionmentioning

confidence: 97%

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Different signaling and functionality of Rac1 and Rac1b in the progression of lung adenocarcinoma

Seiz

Klinke

Scharlibbe

et al. 2019

Biological Chemistry

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Rac1 is a ubiquitously expressed Rho GTPase and an important regulator of the actin cytoskeleton. Its splice variant Rac1b exhibits a 19-amino acid (aa) in-frame insertion and is predominantly active. Both proteins were described in tumorigenesis or metastasis. We investigated the contribution of Rac1 and Rac1b to tumor progression of human non-small-cell lung adenocarcinoma (NSCLA). Rac1 protein was present in 8/8 NSCLA cell lines analyzed, whereas Rac1b was expressed in only 6/8. In wound-healing assays, enhanced green fluorescence protein (EGFP)-Rac1 slightly decreased cell migration, whereas proliferation was increased in both, Rac1- and Rac1b-expressing cells. In the in vivo chorioallantoic invasion model, EGFP-Rac1-expressing cells formed more invasive tumors compared to EGFP-Rac1b. This increased invasiveness correlated with enhanced phosphorylation of p38α, AKT and glycogen synthase kinase 3β (GSK3β), and activation of serum response- and Smad-dependent gene promoters by Rac1. In contrast, Rac1b solely activated the mitogen-activated protein kinase (MAPK) JNK2, together with TCF/LEF1- and nuclear factor kappa B (NFκB)-responsive gene reporters. Rac1b, as Rac1, phosphorylated p38α, AKT and GSK3β. Knockdown of the splicing factor epithelial splicing regulatory protein 1 (ESRP1), which mediates out-splicing of exon 3b from Rac1 pre-messenger RNA, resulted in increased Rac1b messenger RNA (mRNA) and suppression of the epithelial-mesenchymal transition (EMT)-associated transcription factor ZEB1. Our data demonstrate different signaling and functional activities of Rac1 and Rac1b and an important role for Rac1 in lung cancer metastasis.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 97%

Different signaling and functionality of Rac1 and Rac1b in the progression of lung adenocarcinoma

Seiz

Klinke

Scharlibbe

et al. 2019

Biological Chemistry

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“…Rac1b has been associated with poor prognosis in KRAS/BRAF WT metastatic colorectal cancer patients treated with first-line FOLFOX/XELOX therapy (41). Previous studies demonstrate that Rac1b stimulates cell proliferation by enhancing the NF-kB-mediated signaling in colorectal and thyroid cancer cells (12,13,24,42). In our study, we also showed that Rac1b expression provides a proliferative advantage to colorectal cancer cells via activation of the NF-kB pathway.…”

Section: Discussionsupporting

confidence: 77%

RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer

Goka¹,

Chaturvedi²,

Lopez³

et al. 2019

Molecular Cancer Therapeutics

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Resistance to chemotherapy represents a major limitation in the treatment of colorectal cancer. Novel strategies to circumvent resistance are critical to prolonging patient survival. Rac1b, a constitutively activated isoform of the small GTPase Rac1, is upregulated with disease progression and promotes cell proliferation and inhibits apoptosis by activation of NF-kB signaling. Here, we show that Rac1b overexpression correlates with cancer stage and confirmed Rac1b expression is associated with increased growth through enhancing NF-kB activity. Rac1b knockdown reduced cellular proliferation and reduced NF-kB activity. Surprisingly, Rac1b expression and NF-kB activity were upregulated in cells treated with chemotherapeutics, suggesting that Rac1b facilitates chemo-resistance through activation of NF-kB signaling. Knockdown of Rac1b or Rac inhibition increases the sensitivity of the cells to oxaliplatin. When used in combination, inhibition of Rac prevents the increase in NF-kB activity associated with chemotherapy treatment and increases the sensitivity of the cells to oxaliplatin. Although Rac inhibition or oxaliplatin treatment alone reduces the growth of colorectal cancer in vivo, combination therapy results in improved outcomes compared with single agents alone. We provide the first evidence that Rac1b expression confers resistance to chemotherapy in colorectal cancer. Additionally, we show that the use of a Rac inhibitor prevents chemoresistance by blocking activation of chemotherapy induced NF-kB signaling, providing a novel strategy to overcome resistance to chemotherapy in colorectal cancer.

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“…This AP-1 activation by SPSB1 may be explained in part by a recent finding that the SPRY domain of RhTRIM5α is essential for AP-1 but not NF-κB activation 25 . In addition, because ubiquitination of heterogeneous nuclear ribonucleoprotein A1 (HnRNP A1) by SPSB1 induces the expression of Rac1B 26 , which in turn elevates mRNA expression of c-Jun N-terminal kinase 2 and c-JUN 27 , it is plausible that these events cooperate to achieve activation of AP-1-dependent transcription. Because HTLV-1 Tax is a powerful viral trans -acting protein, its incorporation into lentiviral vector particles, if sufficient for its trans -acting functions, could elicit undesired effects in target cells.…”

Section: Discussionmentioning

confidence: 99%

Robust Enhancement of Lentivirus Production by Promoter Activation

Suzuki

Yoshida

Takeuchi

et al. 2018

Sci Rep

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Lentiviral vectors are a valuable tool to deliver exogenous genes for stable expression in cells. While much progress has been made in processing lentiviral vector-containing culture medium, it remains to be explored how the production of lentiviral vector from producer cells can be increased. We initially found that co-expression of the SPRY domain-containing SOCS box protein 1 (SPSB1) promotes the production of human immunodeficiency virus type 1 (HIV-1) and lentiviral vector with increased expression of the Gag and envelope proteins and activation of the HIV-1 LTR and CMV promoter. The presence of AP-1, NF-κB and CREB/ATF recognition sites in these promoters prompted us to utilize human T-lymphotropic virus type 1 (HTLV-1) Tax for lentiviral vector production because Tax activates all these transcription factors. Co-expression of a small amount of Tax markedly increased both the expression of viral structural proteins in producer cells and release of lentiviral vector particles, resulting in a more than 10-fold enhancement of transduction efficiency. Of note, the Tax protein was not detected in the lentiviral vector particles concentrated by ultracentrifugation, supporting the safety of this preparation. Collectively, these results indicate that promoter activation in producer cells represents a promising approach to preparing high-titer lentiviral vectors.

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Rac1b enhances cell survival through activation of the JNK2/c-JUN/Cyclin-D1 and AKT2/MCL1 pathways

Cited by 23 publications

References 60 publications

Different signaling and functionality of Rac1 and Rac1b in the progression of lung adenocarcinoma

Different signaling and functionality of Rac1 and Rac1b in the progression of lung adenocarcinoma

RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer

Robust Enhancement of Lentivirus Production by Promoter Activation

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