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Title: Interplay of protein misfolding pathway and unfolded-protein response in acute promyelocytic leukemia
Authors: Khan, M. 
Keywords: acute promyelocytic leukemia
molecular target
nuclear receptor corepressor
promyelocytic leukemia retinoic acid receptor
protein misfolding
Issue Date: Aug-2010
Source: Khan, M. (2010-08). Interplay of protein misfolding pathway and unfolded-protein response in acute promyelocytic leukemia. Expert Review of Proteomics 7 (4) : 591-600. ScholarBank@NUS Repository.
Abstract: Protein misfolding has traditionally been linked to the pathogenesis of various neurodegenerative diseases. However, emerging evidence from various laboratories, including ours, suggests that protein misfolding may also play a fundamental role in some malignancies, particularly those caused by fusion oncoprotein generated from chromosomal translocation. Promyelocytic leukemia (PML) fused to the retinoic acid receptor (RAR) is a fusion oncoprotein linked to the transformation of acute promyelocytic leukemia (APL), and is not only a misfolded protein itself, but also promotes misfolding of nuclear receptor corepressor (N-CoR) protein, a corepressor essential for the growth-suppressive function of several tumor-suppressor proteins. PML-RAR promotes misfolding of N-CoR by inducing aberrant post-translational modification, which destabilizes its core and promotes instability. Misfolded N-CoR, thus, contributes to differentiation arrest and survival of APL cells through loss-of-function and aberrant gain-of-function properties. Therapeutic restoration of N-CoR conformation and function with conformation-modifying agents not only releases this differentiation arrest but also sensitizes APL cells to programmed cell death. These findings illustrate the potential of the misfolded N-CoR protein as a conformation-based drugable molecular target for APL, and highlights the promise of various conformation-modifying agents as novel therapeutics for APL. Protein conformational rearrangement, resulting from an inherited or acquired genetic alteration, could be a common pathological phenomenon contributing to transformation in different types of leukemias and solid tumors and, therefore, could serve as a common ground for designing a unifying diagnostic as well as therapeutic approach for a widely diverse disease such as cancer. To that end, APL could serve as a model for the development of a novel conformation-based therapeutic approach for other malignant diseases. © 2010 Expert Reviews Ltd.
Source Title: Expert Review of Proteomics
ISSN: 14789450
DOI: 10.1586/epr.10.38
Appears in Collections:Staff Publications

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