HDAC Inhibitors as Epigenetic Regulators

NPM (also known as NPM1), encodes for a protein which is involved in the regulation of cell division, DNA repair, transcription and genomic stability [14]. and encodes for a polypeptid of 1620 amino acid which undergoes to post-translational modifications generating a mature ALK protein of approximately 200C220?kDa [2, 3]. The ALK mature protein is a classical receptor tyrosine kinase that comprises an extracellular ligand-binding domain of 1030 aminoacids (aa), a transmembrane domain (28 aa), and an intracellular tyrosine kinase domain (561 aa) [4]. The kinase domain shares with the other kinases of the same family the 3-tyrosine motif (Tyr1278, Tyr1282 and Tyr1283) which is located in the activation loop and represent the major auto-phosphorylation site of kinase activity [5, 6] (Fig.?1). ALK becomes activated only upon ligand-induced homo-dimerization, and inactivated through de-phosphorylation by receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) in the absence of the ligand [7]. Two proteins, midkine and pleiotrophin, have been reported to be activating ligands for mammalian ALK [8], although they are not specific for ALK [9]. Open in a separate window Fig. 1 Structure of ALK protein. The human ALK protein is a polypeptid of 1620 amino acid. The ALK mature Cav2.3 protein is a classical receptor tyrosine kinase that comprises an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain which harbors the 3-tyrosine motif (Tyr1278, Tyr1282 and Cyclosporin H Tyr1283) which represents the major auto-phosphorylation site regulating kinase activity ALK activates multiple pathways, including phospholipase C , Janus kinase (JAK)-signal transducer and activator of transcription (STAT), Phosphoinositide 3-kinase (PI3K)-AKT, mammalian target of rapamycin (mTOR), sonic hedgehog, JUNB, CRKL-C3G (also known as RAPGEF1)-RAP1 GTPase and mitogen-activated protein kinase (MAPK) signaling cascades, which affect cell growth, transformation and anti-apoptotic signaling [9] (Fig.?2). Open in a separate window Fig. 2 ALK signaling pathway. ALK activates multiple pathways, including phospholipase C , Janus kinase (JAK)-signal transducer and activator of transcription (STAT), PI3K-AKT, mTOR, sonic hedgehog (SMO and GLI), and MAPK signaling cascades, which affect cell growth, transformation and anti-apoptotic signaling. Cyclosporin H Receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) inactivates ALK through de-phosphorylation ALK is highly conserved across species. ALK mRNA expression is present [10] in the adult human brain, where it is thought to play a role in the development and function of the nervous system, and it is also expressed in small intestine, testis, prostate, and colon whereas human lymphoid tissues and cells, lung and other organs are excluded. The first identification of ALK occurred in anaplastic large cell lymphoma (ALCL) as the product of a gene rearrangement [10, 11]. Since then, rearrangement, mutations, or amplification was discovered in a Cyclosporin H series of tumors including lymphoma, neuroblastoma, and non-small cell lung cancer (NSCLC) [12]. So far, 21 different genes have been described as being translocated with and, in addition to this complexity, within the different fusion there are several breakpoint variants. Different fusion proteins may be responsible for different proliferation rates, colony formation, invasion and tumorigenicity capabilities, leading to activation of various signaling pathways. The 70C80% of all ALK-positive ALCL patients present the gene (2p23) and the (nucleolar phosphoprotein B23, numatrin) gene (5q35) translocation [13] with several t(2;5) breakpoint variants described. NPM (also known as NPM1), encodes for a protein which is involved in the regulation of cell division, DNA repair, transcription and genomic stability [14]. The NPM-ALK chimeric protein is constitutively expressed from the NPM promoter, leading to the overexpression of the ALK catalytic domain. Many other rearrangements involving the gene have recently been shown to be associated with ALCL, including (([15]. Of interest, the chimeric protein seems to behave as neo-antigent leading to the production of autologous antibodies against chimeric protein, suggesting an immune response to the ALK protein [16]. The t(2;17)(p23;q23) translocation, which generates CLTC-ALK is also found Cyclosporin H in diffuse large B-cell lymphoma (DLBCL) and represents the most frequent chromosomal rearrangement in this disease. A small portion (0.5C1%) of DLBCLs display the NPM-ALK fusion protein or other fusion proteins such as Sequestosome 1 (SQSTM1)-ALK and SEC31A-ALK. Inflammatory myofibroblastic tumors (IMT) were the first solid tumor to be associated with translocation. Approximately 50% of IMT display clonal rearrangements of gene fused to or to and genes was identified in about 5% of NSCLC patients [19]; the rearrangement is frequently observed in relatively younger patients, non- or light smokers, and those with adenocarcinoma histology without other Cyclosporin H genetic disorders, such as mutations of the gene [20, 21]. All 13 fusion variants of EML4-ALK contain exons 20C29 of exons (2, 6, 13, 14, 15, 17, 18, and 20). Other ALK fusion.