[The kinome and glucocorticoid-induced apoptosis].
In this perspective, I discuss the complex interplay between GC signaling and the kinome that ultimately determines the cell fate after GC treatment. Apoptosis ensues when the cell express sufficient levels of GR and Bim together with a kinome favoring GSK3 activation. Protein kinases that prevent Bim up-regulation and/or inhibit GSK3, confer GC-resistance on the cell. GC-resistance may be overcome in T and B lymphoid malignancies by inhibiting the JNK, Src, PI3K, Akt or mTOR survival pathways. Both staurosporine and rapamycin have recently been proved efficient to sensitize resistant T and B malignant cells to GC-induced apoptosis. This is a proof-of-principle that it is possible to improve GC therapy by altering the cell's kinome.
Sionov
Ronit Vogt
RV
The Lautenberg Center of Immunology, Institute of Medical Research, Faculty of Medicine, Hebrew University, Jerusalem, Israel. sionov@cc.huji.ac.il
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D005938:Glucocorticoids / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007945:Leukemia, Lymphoid / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D005938:Glucocorticoids; D038362:Glycogen Synthase Kinase 3; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011965:Receptors, Glucocorticoid; D058570:TOR Serine-Threonine Kinases; C000606775:BCL2L11 protein, human; C546842:MTOR protein, human