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IL-24 induces apoptosis of chronic lymphocytic leukemia B cells engaged into the cell cycle through dephosphorylation of STAT3 and stabilization of p53 expression Sainz-Perez A; Gary-Gouy H; Gaudin F; Maarof G; Marfaing-Koka A; de Revel T; Dalloul AJ Immunol 2008[Nov]; 181 (9): 6051-60Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of long-lived monoclonal B cells mostly arrested at the G(0)/G(1) phase of the cell cycle. CLL cells strongly express intracellular melanoma differentiation-associated gene-7 (MDA7)/IL-24. However, adenovirus-delivered MDA7 was reported to be cytotoxic in several tumor cell lines. We report herein that rIL-24 alone had no effect; however, sequential incubation with rIL-2 and rIL-24 reduced thymidine incorporation by 50% and induced apoptosis of CLL cells in S and G(2)/M phases of the cell cycle, but not of normal adult blood or tonsil B cells. IL-24 stimulated STAT3 phosphorylation in IL-24R1-transfected cells but not in normal or CLL B cells. In contrast, IL-24 reversed the IL-2-induced phosphorylation of STAT3 in CLL, and this effect was neutralized by anti-IL-24 Ab. Phospho- (P)STAT3 inhibition induced by IL-24 was reversed by pervanadate, an inhibitor of tyrosine phosphatases. The addition of rIL-24 to IL-2-activated CLL B cells resulted in increases of transcription, protein synthesis. and phosphorylation of p53. The biological effects of IL-24 were reversed by the p53 inhibitor pifithrin-alpha and partly by the caspase inhibitor zvad. Troglitazone (a protein tyrosine phosphatase, PTP1B activator) phosphatase inhibited PSTAT3 and augmented p53 expression. PSTAT3 is a transcriptional repressor of p53, and therefore IL-24 induction of p53 secondary to PSTAT3 dephosphorylation may be sensed as a stress signal and promote apoptosis in cycling cells. This model explains why IL-24 can protect some resting/differentiated cells and be deleterious to proliferating cells.|Adult[MESH]|Apoptosis/*immunology[MESH]|B-Lymphocytes/immunology/metabolism/*pathology[MESH]|Cell Cycle/*immunology[MESH]|Cell Line, Tumor[MESH]|Cell Proliferation[MESH]|Humans[MESH]|Interleukin-2/antagonists & inhibitors/physiology[MESH]|Interleukins/*physiology[MESH]|Leukemia, Lymphocytic, Chronic, B-Cell/immunology/metabolism/*pathology[MESH]|Lymphocyte Activation/immunology[MESH]|Phosphorylation/immunology[MESH]|Recombinant Proteins/pharmacology[MESH]|STAT3 Transcription Factor/*metabolism[MESH]|Thymidine/antagonists & inhibitors/metabolism[MESH]|Tumor Suppressor Protein p53/biosynthesis/*genetics/*metabolism[MESH] |
