Regulation of Bcl2 phosphorylation and potential significance for leukemic cell chemoresistance.
Although considered tightly linked, the linkage effectors for proliferation and antiapoptotic signaling pathways are not clear. Phosphorylation of Bcl2 at serine 70 is required for suppression of apoptosis in interleukin 3 (IL-3)-dependent myeloid cells deprived of IL-3 or treated with antileukemic drugs and can result from agonist activation of mitochondrial protein kinase C alpha (PKCalpha). However, we have recently found that high concentrations of staurosporine up to 1 microM: can only partially inhibit IL-3-stimulated Bcl2 phosphorylation but completely block PKCalpha-mediated Bcl2 phosphorylation in vitro, indicating the existence of a non-PKC, staurosporine-resistant Bcl2 kinase (SRK). Although the RAF-1MEK-1-mitogen-activated protein kinase (MAPK) cascade is required for factor-dependent mitogenic signaling, a direct role in antiapoptosis signaling is not clear. In particular, the role of phosphorylation in the regulation of death substrates is not yet clear. Our findings indicate a potential role for the MEK/MAPK pathway in addition to PKC in antiapoptosis signaling, involving Bcl2 phosphorylation that features a role for extracellular signal-regulated kinase (ERK)1 and 2 as SRKs. These findings indicate a novel role for ERK1 and 2 as molecular links between proliferative and survival signaling and may, at least in part, explain the apparent paradox by which Bcl2 may suppress staurosporine-induced apoptosis. Although the effect of phosphorylation on Bcl2 function is not clear, effector molecules that regulate Bcl2 phosphorylation may have clinical significance in patients with acute myelogenous leukemia (AML) who express detectable levels of Bcl2. Preliminary findings suggest that expression of PKCalpha, ERK2, and Bax in leukemic blast cells from patients with AML, although individually not prognostic, appears to have potential clinical value in predicting chemoresistance and survival outcomes.
Deng
X
X
University of Florida Shands Cancer Center, Gainesville 32610, USA.
Kornblau
S M
SM
Ruvolo
P P
PP
May
W S
WS
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007377:Interleukin-3 / Q000502:physiology; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D051571:Protein Kinase C-alpha; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D017346:Protein Serine-Threonine Kinases; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019311:Staurosporine