Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis or programmed cell death is observed in a variety of organisms and tissues and is characterized by distinct morphologic changes to the cell. Although early indicators of this process have been described, their functional relevance remains unknown. We have used two-dimensional gel electrophoresis to look for characteristic and consistent changes in the phosphorylation state of proteins during apoptosis, induced by different agents, in the B cell lymphoma line, BM13674, and the T cell leukemia line, CEM-C7. We report that apoptosis induced by either heat treatment or by ionizing radiation exposure is accompanied by dephosphorylation of a limited number of specific proteins. The pattern of dephosphorylation was similar after both treatments in BM13674 cells. In CEM-C7 cells, dephosphorylation was also observed after heat and irradiation. One of these proteins corresponded to one dephosphorylated in BM13674 cells. Okadaic acid, an inhibitor of phosphatases 1, 2A, and, to a lesser extent, 2B, prevented apoptosis in all cases and inhibited dephosphorylation of this common protein as well as some of the others. It seems likely that activation of a phosphatase(s) or loss of activity of a kinase is of central importance in apoptosis in these systems.
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PMID:Specific protein dephosphorylation in apoptosis induced by ionizing radiation and heat shock in human lymphoid tumor lines. 154 32

Chronic lymphocytic leukemia (CLL) cells, but not peripheral blood T cells, undergo apoptosis following treatment with inhibitors of type 4 cyclic nucleotide phosphodiesterase (PDE4), a process that correlates dose dependently with elevation of adenosine 3',5'-cyclic monophosphate (cAMP) in leukemic cells. We show that treatment of CLL cells with rolipram, a prototypic PDE4 inhibitor, and forskolin, an adenylate cyclase activator, induces mitochondrial depolarization, release of cytochrome c into the cytosol, caspase-9 and -3 activation, and cleavage of poly(adenosine diphosphate [ADP]-ribose)polymerase. Inhibitors of caspase-9, but not caspase-8, block rolipram/forskolin-induced CLL apoptosis. In a subset of CLL patients, B-cell lymphoma 2 (Bcl-2)-associated death promoter homolog (Bad), a proapoptotic Bcl-2 family member that when phosphorylated on specific serine residues is sequestered in the cytosol by 14-3-3, was dephosphorylated at Ser112 following rolipram/forskolin treatment of leukemic cells. Rolipram/forskolin treatment also induced Bad to accumulate in CLL heavy-membrane fractions, consistent with Bad translocation to mitochondria. To determine the mechanism for rolipram/forskolin-induced Bad dephosphorylation, we examined CLL phosphatase activity. Rolipram/forskolin treatment augmented protein phosphatase 2A (PP2A) activity, as well as levels of immunoreactive PP2A catalytic subunit. Treatment of CLL cells with a concentration of okadaic acid (5 nM) that selectively inhibits PP2A, reduced both rolipram/forskolin-induced mitochondrial cytochrome c release and mitochondrial depolarization. Okadaic acid restored Bad Ser112 phosphorylation and Bad association with 14-3-3 in rolipram/forskolin-treated CLL cells. These results suggest that PDE4 inhibitors may induce CLL apoptosis by activating PP2A-induced dephosphorylation of proapoptotic BH3-only Bcl-2 family members such as Bad.
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PMID:PDE4 inhibitors activate a mitochondrial apoptotic pathway in chronic lymphocytic leukemia cells that is regulated by protein phosphatase 2A. 1253 92