Nuclear Factor Kappa-B: Bridging Inflammation and Cancer
Surinder K. Batra, Moorthy P. Ponnusamy in Gene Regulation and Therapeutics for Cancer, 2021
NF-κB has been shown to control proliferation of normal as well as tumor cells by binding to the promoter of genes responsible for cell proliferation. Study published by Brantley and colleagues stated that NF-κB induces proliferation of mammary epithelial cells, suggesting the involvement of NF-κB in the development of mammary glands [90]. In triple negative breast cancer cells, NF-κB has been shown to exhibit trans-activity as it binds upstream of CD44 promoter and induces tumor cell proliferation [91]. Transformed cells grow continuously, circumventing cell cycle check, and NF-κB signaling indirectly controls cancer cell cycle progression by upregulating the expression of cyclin D, a regulator of G1 checkpoint control [92]. Furthermore, it has been shown that Rac1, a small GTPase, induces lung cancer cell proliferation, possibly through NF-κB activation [93].
Articular Cartilage Development
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi in Articular Cartilage, 2017
Rho family small GTPases are activated by switching from an inactive GDP-bound molecule to an active GTP-bound form. Switching to the active form is controlled by guanine nucleotide exchange factors (GEFs), while switching to the inactive form is regulated by GTPase activating proteins (GAPs). GEFs and GAPs are under the control of a multitude of cell surface receptors, including integrins, serine/threonine and tyrosine kinase receptors, and GPCRs. They link extracellular matrix signaling to changes in the cytoskeleton and cell shape.
Exchange Factors
Juan Carlos Lacal, Frank McCormick in The ras Superfamily of GTPases, 2017
In addition to proteins that enhance the rate of exchange of nucleotide on ras-like proteins, it is clearly possible that other proteins might exist that have other effects on nucleotide exchange. In the Chapter 27 by Takai a family of proteins that inhibit guanine nucleotide exchange on ras-related proteins are described: these have been termed GDI for guanine dissociation inhibitors. Whether these proteins are important in controlling the activation state of small GTPases in whole cells is not yet clear.
Activation of the Small GTPase Rap1 Inhibits Choroidal Neovascularization by Regulating Cell Junctions and ROS Generation in Rats
Published in Current Eye Research, 2018
Jiajia Li, Rong Zhang, Caixia Wang, Xin Wang, Man Xu, Jingxue Ma, Qingli Shang
The RPE maintains the outer blood-retinal barrier. Intact barrier integrity is important for the health and function of the retinal photoreceptors and choriocapillaris.14 The barrier comprises a single layer of epithelium cells that have tight junctions. Impairment of junctional regulation interferes with compartmentalization of angiogenic agonists normally secreted from the RPE basal aspect, and inhibitors secreted from the apical aspect, by permitting movement of factors to other compartments.15 This change in concentrations of angiogenic factors such as VEGF activates motile CECs. Tight junctions consist of multiprotein complexes including transmembrane protein components, such as occludin and cadherins, and cytoplasmic protein components, such as ZO-1 and β-, α-, and p120-catenin. Some of these bind to the actin cytoskeleton.16 Of the signaling proteins involved in junctional regulation, small GTPases are focused because of their ability to cycle between active and inactive states. Small GTPases of the Rho family regulate cell junctions by affecting actin cytoskeleton remodeling.17,18
Ras-Mediated Activation of NF-κB and DNA Damage Response in Carcinogenesis
Published in Cancer Investigation, 2020
There are now strong evidences that a few oncogenes such as Ras and c-Myc may be responsible in all three major stages of cancer i.e., early, intermediate and late (62,63). Ras is a G protein, or a guanosine-nucleotide-binding protein. The Ras protein family belongs to the class of proteins called small GTPase that are involved in cellular transduction transmitting signals within cells (Figures 2 and 3). This gene family consists of H-ras, K-ras, and N-ras which encode a 21 kD protein and possess guanosine triphosphate (GTP) activity (64–66). The molecular mechanism of Ras depends on the family of small G-proteins that function as signaling switches with active and “inactive” states. In the off state it is bound to the nucleotide guanosine diphosphate (GDP), while in the on state, Ras is bound to guanosine triphosphate (GTP), which has an extra phosphate group as compared to GDP. When released, the switch regions relax causing a conformational change in the inactivate state. Hence, activation and deactivation of Ras and other small G proteins are controlled by cycling between the active GTP-bound and inactive GDP-bound forms (67). The exchange of bound nucleotide is facilitated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). GAPs accelerate Ras inactivation by activating its GTPase activity and GEFs catalyze a reaction, which releases GDP from Ras, thus GEFs facilitate Ras activation. The balance between GEF and GAP activity determines the guanine nucleotide status of Ras, thereby regulating Ras activity (68,69).
The role of small GTPase Rac1 in ionizing radiation-induced testicular damage
Published in International Journal of Radiation Biology, 2022
Yasar Aysun Manisaligil, Mukaddes Gumustekin, Serap Cilaker Micili, Cemre Ural, Zahide Cavdar, Gizem Sisman, Aysegul Yurt
Small GTPases are involved in various physiological and pathological events such as cell growth, cytoskeleton reconstruction, protein kinase activation, ROS generation and regulation of endothelial permeability. In addition to two cytosolic proteins (p47phox, p67phox) small GTPase Rac1 is also required for the activation of NADPH oxidase in phagocytic cells (Takai et al. 2001). Furthermore, Rac1 has other cell cycle roles, cell adhesion, actin-dependent motility, and epithelial differentiation. The expression and/or activity of Rac1 has been shown to increase under pathological conditions such as oxidative stress and apoptosis (Boehm et al. 1999; Pervaiz et al. 2001). It is thought that Rac1 may play a role in radiation-induced damage considering its role in the generation of ROS and, as a subunit of the NADPH oxidase enzyme, its contribution in the generation of free radicals. In this study, we aimed to investigate the role of small GTPase Rac1 molecule in acute and late effects of low, medium and high dose radiation exposures (administered during diagnosis and/or treatment) on the testicular tissue.
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