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JNCI Monographs 2000 2000(28):30-37;
© 2000 by Oxford University Press
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Journal of the National Cancer Institute Monographs, No. 28, 30-37, 2000
© 2000 Oxford University Press

Regulation of Bcl2 Phosphorylation and Potential Significance for Leukemic Cell Chemoresistance

Presented at the International Symposium on HIV, Leukemia, and Opportunistic Cancers.

Xingming Deng, Steven M. Kornblau, Peter P. Ruvolo, W. Stratford May, Jr.

Affiliations of authors: X. Deng, P. P. Ruvolo, W. S. May, Jr., University of Florida Shands Cancer Center, Gainesville; S. M. Kornblau, The University of Texas M. D. Anderson Cancer Center, Houston.

Correspondence to: W. Stratford May, Jr., M.D., Ph.D., University of Florida Shands Cancer Center, Box 100232, Gainesville, FL 32610-0232 (e-mail: smay{at}ufscc.ufl.edu).

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} (PKC{alpha}). However, we have recently found that high concentrations of staurosporine up to 1 µM can only partially inhibit IL-3-stimulated Bcl2 phosphorylation but completely block PKC{alpha}-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 PKC{alpha}, 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.


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