The role of Rac1 in the regulation of NF-kB activity, cell proliferation, and cell migration in non-small cell lung carcinoma

Gastonguay, Adam; Berg, Tracy J.; Hauser, Andrew D.; Schuld, Nathan J.; Lorimer, Ellen L.; Williams, Carol L.

doi:10.4161/cbt.20082

Cited by 91 publications

(82 citation statements)

References 44 publications

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“…6A). Activation of RhoA, as well as other small GTPases, can promote NF-B activity in several cancers (31,33,35,36). Loss of SmgGDS interactions with these GTPases because of DiRas1 expression can likely lead to decreased NF-B activation in cancer cells (Figs.…”

Section: Discussionmentioning

confidence: 99%

The Tumor-suppressive Small GTPase DiRas1 Binds the Noncanonical Guanine Nucleotide Exchange Factor SmgGDS and Antagonizes SmgGDS Interactions with Oncogenic Small GTPases

Bergom

Hauser

Rymaszewski

et al. 2016

Journal of Biological Chemistry

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The small GTPase DiRas1 has tumor-suppressive activities, unlike the oncogenic properties more common to small GTPases such as K-Ras and RhoA. Although DiRas1 has been found to be a tumor suppressor in gliomas and esophageal squamous cell carcinomas, the mechanisms by which it inhibits malignant phenotypes have not been fully determined. In this study, we demonstrate that DiRas1 binds to SmgGDS, a protein that promotes the activation of several oncogenic GTPases. In silico docking studies predict that DiRas1 binds to SmgGDS in a manner similar to other small GTPases. SmgGDS is a guanine nucleotide exchange factor for RhoA, but we report here that SmgGDS does not mediate GDP/ GTP exchange on DiRas1. Intriguingly, DiRas1 acts similarly to a dominant-negative small GTPase, binding to SmgGDS and inhibiting SmgGDS binding to other small GTPases, including K-Ras4B, RhoA, and Rap1A. DiRas1 is expressed in normal breast tissue, but its expression is decreased in most breast cancers, similar to its family member DiRas3 (ARHI). DiRas1 inhibits RhoA-and Smg-GDS-mediated NF-B transcriptional activity in HEK293T cells. We also report that DiRas1 suppresses basal NF-B activation in breast cancer and glioblastoma cell lines. Taken together, our data support a model in which DiRas1 expression inhibits malignant features of cancers in part by nonproductively binding to SmgGDS and inhibiting the binding of other small GTPases to SmgGDS.

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Section: Discussionmentioning

confidence: 99%

The Tumor-suppressive Small GTPase DiRas1 Binds the Noncanonical Guanine Nucleotide Exchange Factor SmgGDS and Antagonizes SmgGDS Interactions with Oncogenic Small GTPases

Bergom

Hauser

Rymaszewski

et al. 2016

Journal of Biological Chemistry

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“…The evidence includes the following: 1) NF-B inhibition significantly attenuated H 2 O 2 and/or PKC activation-induced decrease in TRPC6 protein expression, 2) NF-B activation could mimic the H 2 O 2 /PKC effect on TRPC6 expression, 3) PKC could activate NF-B, stimulate its nuclear translocation, and further its binding to the TRPC6 promoter, and finally 4) activation and inhibition of NF-B significantly suppressed and enhanced TRPC6-mediated Ca 2ϩ entry, respectively. NF-B is a transcription factor that participates in a wide range of cellular responses, such as inflammation and proliferation when a cell is insulted by pathogenic stimuli (43,48,49). Like NF-B, TRPC6 is also involved in inflammatory responses (50,51), and TRPC6-associated Ca 2ϩ entry is also associated with cell proliferation (2,52,53).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Factor κB Mediates Suppression of Canonical Transient Receptor Potential 6 Expression by Reactive Oxygen Species and Protein Kinase C in Kidney Cells

Wang¹,

Ding²,

Chaudhari³

et al. 2013

Journal of Biological Chemistry

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Background: TRPC6 expression in glomerular cells is suppressed by ROS through a PKC mechanism. Results: Activation and inhibition of NF-B could mimic and inhibit the ROS/PKC effect on TRPC6 expression, respectively. Conclusion: NF-B mediates the inhibitory effect of ROS/PKC on TRPC6 expression in mesangial cells. Significance: This study delineated a molecular mechanism for regulation of TRPC6 at the transcriptional level.

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“…Several downstream effectors exert the biologic effects of Rac1. Rac1 activates NF-kB transcription factors, leading to inflammatory responses, cell growth, and apoptotic suppression (39). Both the N-and C-terminus of Nischarin interacts with Rac1 in its active state to disrupt the NF-kB pathway and thus repress cyclin D1, the promoter associated with malignancy ( Fig.…”

Section: Nischarin Inhibits Cell Migration and Invasionmentioning

confidence: 99%

Breast Cancer Tumor Suppressors: A Special Emphasis on Novel Protein Nischarin

Maziveyi

Alahari

2015

Cancer Research

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Tumor suppressor genes regulate cell growth and prevent spontaneous proliferation that could lead to aberrant tissue function. Deletions and mutations of these genes typically lead to progression through the cell-cycle checkpoints, as well as increased cell migration. Studies of these proteins are important as they may provide potential treatments for breast cancers. In this review, we discuss a comprehensive overview on Nischarin, a novel protein discovered by our laboratory. Nischarin, or imidazoline receptor antisera-selected protein, is a protein involved in a vast number of cellular processes, including neuronal protection and hypotension. The NISCH promoter experiences hypermethylation in several cancers, whereas some highly aggressive breast cancer cells exhibit genomic loss of the NISCH locus. Furthermore, we discuss data illustrating a novel role of Nischarin as a tumor suppressor in breast cancer. Analysis of this new paradigm may shed light on various clinical questions. Finally, the therapeutic potential of Nischarin is discussed.

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The role of Rac1 in the regulation of NF-kB activity, cell proliferation, and cell migration in non-small cell lung carcinoma

Cited by 91 publications

References 44 publications

The Tumor-suppressive Small GTPase DiRas1 Binds the Noncanonical Guanine Nucleotide Exchange Factor SmgGDS and Antagonizes SmgGDS Interactions with Oncogenic Small GTPases

The Tumor-suppressive Small GTPase DiRas1 Binds the Noncanonical Guanine Nucleotide Exchange Factor SmgGDS and Antagonizes SmgGDS Interactions with Oncogenic Small GTPases

Nuclear Factor κB Mediates Suppression of Canonical Transient Receptor Potential 6 Expression by Reactive Oxygen Species and Protein Kinase C in Kidney Cells

Breast Cancer Tumor Suppressors: A Special Emphasis on Novel Protein Nischarin

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