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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The Inhibitors of Apoptosis Proteins (IAPs) are a family of functionally and structurally related proteins that serve as endogenous inhibitors of programmed cell death (apoptosis). A common feature of all IAPs is the presence of a BIR (Baculovirus IAP Repeat, a ~70 amino acid domain). The human IAP family consists of eight members, and IAP homologs have been identified in numerous organisms. The best characterized IAP is XIAP, which binds Caspases-3, Caspase-7, and Caspase-9, thereby inhibiting their activation and preventing apoptosis. The activity of XIAP is blocked by binding to the DIABLO (Smac) and HTRA2 (Omi) proteins released from mitochondria following pro-apoptotic stimuli. The cIAP1 and cIAP2 proteins have also been shown to bind caspases, although how the IAPs inhibit apoptosis at the molecular level is not completely understood.
Antileukemic Treatment Targeted at Apoptosis Regulators
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Simone Fulda, Klaus-Michael Debatin
One promising therapeutic strategy directed at apoptosis regulators is the neutralization of IAPs. IAPs are a family of endogenous caspase inhibitors and comprise eight human analogs, which are XIAP, cIAP1, cIAP2, survivin, livin or melanoma-IAP (ML-IAP), apollon, NAIP, and ILP-2 (26). Among the IAP family members, XIAP is best known for its antiapoptotic function (65). XIAP blocks apoptosis by binding to active caspase-3 and -7 and also by interfering with caspase-9 activation (26). In addition, XIAP inhibits apoptosis via mechanisms unrelated to its ability to inhibit caspases. For example, XIAP can activate the NF-κB pathway by forming a complex with the TAK1 kinase and its cofactor TAB1 (66–69). Mechanistically, the XIAP-mediated NF-κB activation can be dissociated from its caspase-inhibitory effects and requires the E3 ubiquitin ligase activity of XIAP (66–69). The role of survivin in the regulation of apoptosis and proliferation is more complex compared with other IAP family proteins (70). Besides its role as a regulator of apoptosis, survivin is also involved in the control of mitosis (70).
Immunology (primary Immunodeficiency Syndromes
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephan Strobel, Alison M. Jones
X-linked lymphoproliferative disease (XLP) type 1, also known as Duncan syndrome or Purtilo syndrome, is characterised by inability to mount an appropriate immune response to EBV infection (infectious mononucleosis) and sometimes other viruses. XLP-1 is caused by mutations in a gene known as SH2D1A, which encodes SLAM-associated protein (SAP). A similar syndrome, XLP type 2, is caused by mutations in XIAP (X-linked inhibitor of apoptosis protein), and is associated with a high incidence of inflammatory bowel disease.
The roles of TPL in hematological malignancies
Published in Hematology, 2023
Tingyun Xu, Yiwei Zhu, Shuaishuai Ge, Song-Bai Liu
Apoptosis is the main antitumor mechanism of TPL. Multiple signaling pathways and mechanisms are involved in mediating the proapoptotic effect of TPL (Figure 1). XIAP (X-linked inhibitor of apoptosis protein) is a natural intracellular caspase inhibitor and is highly expressed in a variety of leukemia cell lines and acute myelocytic leukemia (AML) blasts [10, 11]. TPL can induce caspase-dependent apoptosis in several AML cell lines and AML blasts by reducing the expression of XIAP and MCL-1 [12], and promoting cytochrome C release to upregulate caspase-dependent apoptotic pathways [13, 14]. The p53 signaling pathway is also involved in this process [15]. MDM2 is an intracellular negative regulator of p53. TPL induces AML cell apoptosis by reducing MDM2 expression to disrupt MDM2-p53 homeostasis [16], thereby promoting p53 activation and upregulating the expression of the downstream death receptor DR5 [17]. AML cells are relatively resistant to tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL), which can be overcome by TPL by downregulating XIAP and activating the P53 signaling pathway [18, 19]. Therefore, TPL combined with TRAIL may achieve a better effect in treating AML.
Circ_0000527 Promotes Retinoblastoma Progression through Modulating miR-98-5p/XIAP Pathway
Published in Current Eye Research, 2021
Binke Yu, Jifei Zhao, Yongxiao Dong
Moreover, we speculated that miR-98-5p and XIAP had a targeting relationship based on the prediction software, which was verified by dual-luciferase reporter and RIP assays. Besides, dysregulation of apoptosis is a hallmark of human cancer.34 XIAP belongs to the inhibitor of apoptosis proteins (IAPs) family and blocks apoptosis by inhibiting caspase activity.35 Recent studies disclosed that biomolecules that specifically bind and degrade XIAP might become promising targets for cancer therapy by inducing cell apoptosis.36 In retinoblastoma, miR-214-3p enhanced multi-drug sensitivity and facilitated cell apoptosis via negatively regulating ABCB1 and XIAP.37 In the current study, we demonstrated that miR-98-5p restrained RB development by targeting XIAP.
Apoptosis targeted therapies in acute myeloid leukemia: an update
Published in Expert Review of Hematology, 2020
Somedeb Ball, Gautam Borthakur
The extrinsic pathway is triggered by the binding of signal molecules to the transmembrane death receptors, such as Fas, tumor necrosis factor (TNF), and TNF-related apoptosis-inducing ligand (TRAIL). This interaction results in the formation of a death-inducing signaling complex, with the incorporation of Fas-associated death domain (FADD) or TNF receptor type 1-associated death domain protein (TRADD) and procaspase 8, which in turn gets activated to caspase 8. Activation of other downstream effector caspases (caspases 3 and 7) brings about the degradation of cellular substrates. Several inhibitors of apoptosis proteins (IAP), namely X- linked IAP (XIAP), cellular IAP (cIAP), and survivin inhibit apoptosis at different levels of cascade. Among these, XIAP is more specific for the extrinsic pathway [9,10]. However, XIAP can also inhibit the apoptosome in intrinsic pathway through its effect on caspase 9. Several molecules antagonize the action of IAPs, most prominent being the second mitochondrial-derived activator of caspases (SMAC) [11].