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lüll BiP/GRP78 is an intracellular target for MDA-7/IL-24 induction of cancer-specific apoptosis Gupta P; Walter MR; Su ZZ; Lebedeva IV; Emdad L; Randolph A; Valerie K; Sarkar D; Fisher PBCancer Res 2006[Aug]; 66 (16): 8182-91Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a unique member of the IL-10 gene family that induces cancer-selective growth suppression and apoptosis in a wide spectrum of human cancers in cell culture and animal models. Additionally, recent clinical trials confirm safety and document significant clinical activity of mda-7/IL-24 in patients with diverse solid cancers and melanomas. Despite intensive study the molecular basis of tumor-cell selectivity of mda-7/IL-24 is not well characterized. Using deletion analysis, a specific mutant of MDA-7/IL-24, M4, consisting of amino acids 104 to 206, is described that retains the cancer-specific growth-suppressive and apoptosis-inducing properties of the full-length protein. Employing rationally designed mutational analysis, we show that MDA-7/IL-24 and M4 physically interact with BiP/GRP78 through their C and F helices, localize in the endoplasmic reticulum, and activate p38 MAPK and GADD gene expression, culminating in cancer-selective apoptosis. These studies provide novel mechanistic insights into the discriminating antitumor activity of MDA-7/IL-24 by elucidating BiP/GRP78 as a defined intracellular target of action and present an unparalleled opportunity to develop improved therapeutic versions of this cancer-specific apoptosis-inducing cytokine.|Adenoviridae/genetics[MESH]|Apoptosis[MESH]|Breast Neoplasms/genetics/pathology[MESH]|Cell Line, Tumor[MESH]|Cell Survival[MESH]|DNA Mutational Analysis[MESH]|DNA Primers[MESH]|DNA, Neoplasm/genetics[MESH]|Endoplasmic Reticulum Chaperone BiP[MESH]|Epithelial Cells/physiology[MESH]|Female[MESH]|Gene Expression Regulation, Neoplastic[MESH]|HeLa Cells[MESH]|Heat-Shock Proteins/*genetics[MESH]|Humans[MESH]|Interleukins/*genetics[MESH]|Male[MESH]|Molecular Chaperones/*genetics[MESH]|Mutagenesis[MESH]|Nucleic Acid Conformation[MESH]|Prostate/cytology[MESH]|Recombination, Genetic[MESH]|Sequence Deletion[MESH] |