PI3-kinase regulates survival of chronic lymphocytic leukemia B-cells by preventing caspase 8 activation

Leukemia & Lymphoma
Janet M D Plate

Abstract

Studies to investigate signal transduction pathways that support viability and prevent apoptosis of chronic lymphocytic leukemia cells (CLL) were initiated as a result of microarray cDNA analyses which revealed expression of genes whose products regulate cell cycle progression. Immunoblots revealed translation of several genes including caspases, cyclin D1, and the PI3-kinase dependent, survival kinase, Akt. Akt was found to be activated. Inhibition of PI3-kinase with specific inhibitor, LY294002, led to the induction of apoptosis that was caspase 8 dependent, but independent of Akt as LY294002 did not depress a high basal level of Akt activity found in CLL cells. Phosphorylation of Akt was maintained, enzymatic activity undiminished, and phosphorylation of substrates sustained. Caspases, however were activated, PARP cleaved and DNA fragmented. Caspase inhibitors revealed that initiator caspase 8 was required for classic apoptosis when PI3-kinase was inhibited, and specific activity assays demonstrated its early activation. GSK-3beta a kinase regulated via PI3-kinase dependent, down-stream kinases, was responsible for regulating cyclin D1 levels in CLL cells, but neither GSK-3beta nor calpain was responsible for induction of ap...Continue Reading

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Citations

Jun 25, 2008·Blood·Janet Plate
Oct 10, 2009·Haematologica·Mercè de FriasJoan Gil
Mar 14, 2012·Expert Opinion on Investigational Drugs·Kumudha Balakrishnan, Varsha Gandhi
Apr 9, 2013·Hematology/oncology Clinics of North America·Yair HerishanuAdrian Wiestner
Dec 21, 2004·Biochemical and Biophysical Research Communications·Young-Lai ChoYoung-Myeong Kim
Jan 23, 2015·Molecular Medicine·Nino PorakishviliPeter M Lydyard
Jul 14, 2011·Molecular and Cellular Biochemistry·Leila R MartinsJoão T Barata
Jan 14, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Zibo SongY Lynn Wang
Mar 10, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Ranadip MandalKlaus Strebhardt

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