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Nuclear Factor Kappa-B: Bridging Inflammation and Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Mohammad Aslam Khan, Girijesh Kumar Patel, Haseeb Zubair, Nikhil Tyagi, Shafquat Azim, Seema Singh, Aamir Ahmad, Ajay Pratap Singh
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].
Exchange Factors
Published in Juan Carlos Lacal, Frank McCormick, 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.
Articular Cartilage Development
Published in Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi, Articular Cartilage, 2017
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi
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.
Probing mutation-induced conformational transformation of the GTP/M-RAS complex through Gaussian accelerated molecular dynamics simulations
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Huayin Bao, Wei Wang, Haibo Sun, Jianzhong Chen
RAS family of small GTPases, mainly including H-, K-, and N-RAS, is the product of the RAS proto-oncogenes. In addition, RAS family of small GTPases is also involved in a number of its relatives, such as Rap1, Rap2, R-RAS, M-RAS, Ral, Rin, Rit, Rheb, etc. These RAS proteins function as a molecular switch by cycling between an active state bound by guanosine triphosphate (GTP) and an inactive state bound by guanosine diphosphate (GDP) in various intracellular signalling pathways regulating cell growth, differentiation, and apoptosis1–7. The hydrolysis reaction of GTP into GDP is accelerated by the GTPase activating proteins (GAPs), which yields an inactive form of the GDP-bound RAS proteins8. The transformation of GDP into GTP is catalysed by guanosine nucleotide exchange factors (GNEFs), resulting in an active state of the GTP-bound RAS proteins7–9. Recently, increasing attentions are paid to these RAS proteins due to their close relations with a variety of human cancers10–13. More previous works suggested that mutation-induced activity of RAS proteins has been frequently detected in cancer patients and some small molecule inhibitors have been designed towards treatments of human cancers14–18. Therefore further probing possible factors of RAS proteins involved in human cancers are of high significance for drug design towards RAS proteins.
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.
Modulation of ABCG2 surface expression by Rab5 and Rab21 to overcome multidrug resistance in cancer cells
Published in Xenobiotica, 2020
ABCG2 is a half transporter; being half the size of a canonical eukaryotic ABC transporter, it forms dimers for its function. ABCG2 is predominantly localised to cell surface, unlike the other ABCG half transporters that are mainly localised to intracellular membranes (Rocchi et al., 2000). Membrane proteins are constantly transported through endocytic and recycling pathways (Mellman & Warren, 2000; Rothman & Wieland, 1996). Endocytosis of ABCG2 is through a clathrin-dependent, caveolin-independent pathway. Internalised ABCG2 has two fates: lysosomal degradation or its recycling back to the plasma membrane (Studzian et al., 2015). Human genome encodes more than 70 Rab GTPases to regulate vesicular traffic (Agola et al., 2011). These proteins constitute the largest family of small GTPases that regulate vesicle formation, translocation, and fusion (Srikanth et al., 2017). All Rab GTPases perform their functions as molecular switches that alternate between two phases: an active, GTP-bound “ON” form and an inactive, GDP-bound “OFF” form. It has been reported that twenty different Rab proteins among seventy mammalian Rab GTPases, are involved in endocytosis and recycling pathways (Agola et al., 2011). Rab5 and Rab21 regulate receptor-mediated endocytosis through clathrin-coated vesicles, sharing common regulatory and effector proteins (Chavrier et al., 1990; Pellinen et al., 2006).