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Farnesyltransferase Inhibitors: Current and Prospective Development for Hematologic Malignancies
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
With respect to other Ras-related proteins, studies in Caenorhabditis elegans demonstrate that FTIs can induce apoptosis by inhibiting the structurally distinct prenyltransferase enzyme Rab-GGT (GGT type II), which prenylates the Ras-related protein Rab (22). Rab proteins regulate endosomal trafficking and, like Ras, require posttranslational prenylation for membrane attachment and function. FTIs abrogate Rab-GGT activity and thereby directly induce p53-independent apoptosis. In addition, FTIs may exert cytotoxicity by inhibiting farnesylation of the Ras-related protein RHEB (Ras homologue enriched in brain). RHEB inhibition, in turn, blocks downstream mTor/S6 kinase signaling (2,3,23).
Noninsulin-Dependent Animal Models of Diabetes Mellitus
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Christopher H. S. McIntosh, Raymond A. Pederson
Reynet and Kahn.382 identified a small GTP-binding protein (rad: Ras-related protein associated with diabetes), and reported that it was overexpressed in skeletal muscle of patients with NIDDM. Rad appears to play a role as a negative regulator of insulin-stimulated glucose transport,384 and overexpression could therefore result in insulin resistance. A polymorphism in the rad gene was initially reported to be associated with NIDDM in American Caucasians, but subsequent studies have not confirmed this observation.13,385 The status of rad is therefore unclear.
Properties of GAP Proteins
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
Most likely, every ras-related protein has a specific GAP, and to date rapi,5-8rho,9rab,10ypt1,11ral,12 and rac13 appear to interact with one, and in some cases with more than one, specific GAP protein, although little is known about their function. Table 1 shows a summary of all the GAP proteins reported thus far. As the individual characteristics of these specific GAPs will be discussed in different chapters of this book, I will concentrate in reviewing all the data available on the mammalian ras pi 20-G AP protein. Excitingly, the product of the gene defective in human neurofibromatosis, NF-117-19 appears to be a new GAP for ras,20 and the current investigations will also be described.
Hyperthermia promotes exosome secretion by regulating Rab7b while increasing drug sensitivity in adriamycin-resistant breast cancer
Published in International Journal of Hyperthermia, 2022
Di Xu, Wen-Juan Tang, Yi-Zhi Zhu, Zhen Liu, Kai Yang, Ming-Xing Liang, Xiu Chen, Yang Wu, Jin-Hai Tang, Wei Zhang
Exosomes are double-layered vesicles that are important mediators of intracellular communication. Exosomes from different cells can not only carry specific protein molecules, but also contain key molecules to perform their functions. Thus, targeting exosome secretion has emerged as an attractive therapeutic target that can be adjusted by various conditions, such as hypoxia, photodynamic treatment, and hydrochloride hydrate GW4869 [46]. Additionally, exosome release is generally associated with early apoptotic events [47]. The complex processes of exosome secretion are regulated by various molecules, such as RAS-related protein (RAB) GTPases [31]. Here, our results showed that Rab7b, a small GTPase that can control transport from early endosomes to late endocytic compartments—such as late endosomes and lysosomes—contributes to the promotion of exosome release by hyperthermia. With high similarity to Rab7, Rab7b controls endosome transport and promotes fusion with the plasma membrane, being localized both to the trans-Golgi network and to the late endosomes [48,49].
Effects of inhibition of phosphodiesterase 3B in pancreatic islets on insulin secretion: a potential link with some stimulatory pathways
Published in Archives of Physiology and Biochemistry, 2021
Agnieszka Kilanowska, Tomasz Szkudelski
Sulfonylureas are widely used in type 2 diabetes to support insulin secretion if the function of β cells is partially retained. To study the potential link between sulfonylureas and inhibition of PDE3B on insulin secretion, pancreatic islets were exposed to glibenclamide and amrinone. Glibenclamide is an agonist for the SUR1 regulatory subunit, a sulfonylurea receptor of the KATP channel in the plasma membrane (Mikhailov et al.2002). Its presence leads to closure of this channel, resulting in membrane depolarization and opening of voltage-gated calcium channels. The increase in intracellular Ca2+ levels initiates the exocytosis of insulin granules. Moreover, the SUR1 subunit influences Epac2 protein which is directly activated by cAMP. Its presence leads to the activation of Rap1 (Ras-proximate-1 or Ras-related protein 1), also known as the small GTPase. Rap1 binds to PLC-ε, thus initiating a PIP2-dependent reaction. The above-described mechanisms lead to insulin exocytosis (Gloerich and Bos 2010 Dzhura et al.2011).
Molecular insights into cancer drug resistance from a proteomics perspective
Published in Expert Review of Proteomics, 2019
Yao An, Li Zhou, Zhao Huang, Edouard C. Nice, Haiyuan Zhang, Canhua Huang
Ovarian carcinoma patients are usually diagnosed at an advanced stage of the disease where there is high lethality [67]. Platinum-based therapy is the front-line treatment for advanced ovarian cancer. Four-Plex iTRAQ labeling was performed on peptides derived from clinical tumor tissues, using LC-MS/MS with an Orbitrap mass spectrometer for proteome and phosphoproteome analyses. Fourteen of the proteins were more abundant in the platinum-resistance group, including ACTN4 and KRT19, whereas RANBP1, IGLL5, and TPMT were higher in the sensitive group. These results show platinum-resistant patients exhibit significant alteration in the pathways of ATP synthesis and Ras-related nuclear protein (Ran) GTPase binding [68]. Ran GTPase is a Ras-related protein that is involved in modulating DNA synthesis, cell cycle regulation, and nuclear-cytoplasmic transportation [69].