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The Major Histocompatibility Complex
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Peptides are carried from proteasomes in the cytoplasm to the ER by members of the ABC (ATP-binding cassette) family of protein transporters. Two major transporters of antigenic peptides (TAP) have been identified in humans, TAP-1 and TAP-2. TAP 1 and 2 are encoded within the MHC class II locus. Expression of TAP and LMP genes may be coordinately regulated by IFNs. Both TAP proteins are necessary for proper antigen processing in the endogenous pathway; they associate to form a heterodimeric complex. It is speculated that the TAP heterodimer translocates cytosolic peptides into the ER lumen where they then bind to MHC class I/β2m. The mechanism of release of the peptide by the transporter is not known.
Therapeutic Targeting of the Melanoma Stem Cell Population
Published in Sanjiv S. Agarwala, Vernon K. Sondak, Melanoma, 2008
Keiran S.M. Smalley, Brijal Desai, Meenhard Herlyn
There are many similarities between stem cells and tumor-initiating cells. Both populations are known to be relatively quiescent and have multiple mechanisms to overcome exogenous genotoxic stimuli through the high expression levels of (ABC) ATP-binding cassette-family drug transporters and an increased capacity for DNA repair. Similarly, both tumor cells and stem cells are able to suppress the activity of p53, following genotoxic insult, leading to reduced levels of apoptosis (18). In addition, both normal stem cells and over 90% of human tumors express the enzyme telomerase, which maintains chromosomal integrity at the chromosome ends, following prolonged rounds of cell proliferation (19).
Dasatinib self-assembled nanoparticles decorated with hyaluronic acid for targeted treatment of tumors to overcome multidrug resistance
Published in Drug Delivery, 2021
Yawen Zhang, Xiangle Zeng, Hairong Wang, Ranran Fan, Yike Hu, Xuejie Hu, Jianchun Li
Multidrug resistance (MDR) is one of the main obstacles to effective chemotherapy of tumor. Mechanisms of MDR production include increased efflux of drugs to reduce intracellular accumulation of drugs, promoting antiapoptotic mechanisms, and repairing DNA damage (Almalik et al., 2013; Koshkin et al., 2013; Singh et al., 2017; Trujillo-Nolasco et al., 2019). Among them, P-glycoprotein (P-gp), as a membrane transporter of the ATP binding cassette family, can pump out substrate drugs through an ATP-dependent mechanism, thereby reducing intracellular drug accumulation, which is one of the main causes of MDR (Chen et al., 2016; Gupta et al., 2017; Li et al., 2017). A variety of P-gp inhibitors such as Pluronic, Verapamil, and TPGS have been discovered (Gottesman et al., 2002; Negi et al., 2019; Xu et al., 2020). Among them, D-α-tocopherol acid polyethylene glycolsuccinate (TPGS), an amphiphilic structure, can self-assemble to form nanoparticles and improve the permeability to cancer cells, making it an ideal nanocarrier (Wang et al., 2016; Popova et al., 2019; Tao et al., 2020).
Pseudoxanthoma elasticum and retinitis pigmentosa: dual diagnosis of recessive conditions with ophthalmological consequences
Published in Ophthalmic Genetics, 2020
Disha Katiyar, Peter Davies, Himanshu Goel
Pseudoxanthoma elasticum (PXE) is an autosomal recessive connective tissue disease with variable systemic manifestations that are a result of mineralisation and fragmentation of elastic fibres (1). The prevalence of PXE is estimated to be between 1:25 000 and 1:100 000 (2). Pathogenic mutations in ABCC6 (OMIM 603234) are associated with PXE. ABCC6 (Chr16p13.1) encodes for multidrug resistance protein six (MRP6) which is a part of the ATP-binding cassette family (2). The highest level of ABCC6 expression is in the liver and kidney cell membranes; for this reason, it is theorised that PXE is a metabolic disease caused by abnormal levels of molecules which play a role in the synthesis of the extracellular matrix (1). Since connective tissue is present throughout the body, the disease manifests with skin, eye and cardiovascular features.
Should patients with symptomatic cholelithiasis before 30 years of age be tested for ABCB4 gene mutations?
Published in Scandinavian Journal of Gastroenterology, 2020
Catarina Gouveia, Margarida Flor de Lima, Flávio Pereira, Bruno Rosa, José Cotter, António Banhudo, Maria Duarte, Alexandre Ferreira, Marília Cravo, Joana Nunes
LPAC syndrome is associated with mutations of the ABCB4/MDR3 gene, located on chromosome 7, locus 21 (7q21). This gene encodes a 1279 amino acid transmembrane protein with 27 coding exons, from the ATP-binding cassette family, which acts as a phosphatidylcholine transporter across the bile canalicular membrane [7]. Mutated proteins result in a decrease of this phospholipid, thus increasing bile lithogenicity due to the supersaturation of cholesterol crystals. In addition, low bile concentration of phospholipids increases the amount of free bile acids that act as potent detergents, leading to bile epithelium inflammation, injury, and cholestasis which explains increased gamma-glutamyltranspeptidase (GGT) [8]. Prevalence of ABCB4 gene variants in patients with LPAC criteria may be as high as 56% [9].