B-cell receptor signaling in chronic lymphocytic leukemia cells is regulated by overexpressed active protein kinase CbetaII.
Signals through the B-cell antigen receptor (BCR) are important for the survival of chronic lymphocytic leukemia (CLL) cells. Therefore, factors that influence these signals have important pathophysiological roles in this disease. One key mediator of BCR signaling is protein kinase C beta (PKCbeta), which regulates the activation of I-kappaB kinases and the deactivation of Bruton tyrosine kinase within the signaling pathways initiated by BCR engagement. The present study demonstrates that overexpression of the PKCbetaII isoform is a feature of CLL cells and that activity of this enzyme strongly correlates with CLL cell response to BCR engagement. Thus, intracellular Ca2+ release and increases in cell survival after BCR cross-linking were significantly greater in CLL patients with low levels than in CLL patients with high levels of active PKCbetaII. Furthermore, BCR-induced Ca2+ fluxes could be restored in CLL patients with high levels of active PKCbetaII by pretreating the cells with the PKCbeta-specific inhibitor LY379196. Conversely, BCR-mediated intracellular Ca2+ release could be inhibited in CLL cells with low levels of active PKCbetaII by pretreatment with the PKC agonist bryostatin. Taken together, these results demonstrate that overexpressed active PKCbetaII plays a role in the regulation and outcome of BCR signals that can be important for the progression of CLL.
Abrams
Simon T
ST
Department of Haematology, University of Liverpool, UK.
Lakum
Tasneem
T
Lin
Ke
K
Jones
Gemma M
GM
Treweeke
Andrew T
AT
Farahani
Mosavar
M
Hughes
Mair
M
Zuzel
Mirko
M
Slupsky
Joseph R
JR
D054713:Bryostatins; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000473:pathology; D018942:Macrolides / Q000494:pharmacology; D008698:Mesylates / Q000494:pharmacology; D011493:Protein Kinase C / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D064546:Protein Kinase C beta; D011758:Pyrroles / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell; D015398:Signal Transduction
C434605:5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate; D054713:Bryostatins; D018942:Macrolides; D008698:Mesylates; D011758:Pyrroles; D011947:Receptors, Antigen, B-Cell; C046785:bryostatin 1; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D002118:Calcium