Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia
| Autor: | Kathryn L. Perry, Karine Z. Oben, Mary K. McKenna, Joseph T. Greene, Roger A. Fleischman, Rajeswaran Mani, Vivek M. Rangnekar, James P. Collard, Sunil K. Noothi, Eric B. Durbin, Jacqueline R. Rivas, Chi Wang, Gerhard C. Hildebrandt, John C. Byrd, Subbarao Bondada, Natarajan Muthusamy, Sara S. Alhakeem |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cyclin-Dependent Kinase Inhibitor p21 Chronic lymphocytic leukemia Immunology PAWR Receptors Antigen B-Cell Biochemistry 03 medical and health sciences LYN Mice Inbred NOD hemic and lymphatic diseases Cell Line Tumor medicine Bruton's tyrosine kinase Animals Humans B cell Lymphoid Neoplasia biology Gene Expression Regulation Leukemic Cell Cycle breakpoint cluster region Cell Biology Hematology medicine.disease Leukemia Lymphocytic Chronic B-Cell Up-Regulation Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Cancer cell Cancer research biology.protein Signal transduction Apoptosis Regulatory Proteins Gene Deletion Signal Transduction |
| Popis: | Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is downregulated in many cancers including renal cell carcinoma, glioblastoma, endometrial, and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from Eµ-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL-derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1-to-S cell-cycle transition. Lack of Par-4 also increased the expression of p21 and delayed CLL growth in Eμ-Tcl1 mice. Par-4 expression in CLL cells required constitutively active B-cell receptor (BCR) signaling, as inhibition of BCR signaling with US Food and Drug Administration (FDA)–approved drugs caused a decrease in Par-4 messenger RNA and protein, and an increase in apoptosis. In particular, activities of Lyn, a Src family kinase, spleen tyrosine kinase, and Bruton tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling. Together, these results suggest that Par-4 may play a novel progrowth rather than proapoptotic role in CLL and could be targeted to enhance the therapeutic effects of BCR-signaling inhibitors. |
| Databáze: | OpenAIRE |
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