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Inhibition of Leukemic Cell Growth by the Protein Kinase C Activator Bryostatin 1 Correlates with the Dephosphorylation of Cyclin-dependent Kinase 2¹

Division of Hematology/Oncology, University of Alabama, Birmingham, Alabama 35294 [C. A., J. B., A. S. K.] and Medical Oncology, Seattle VA Medical Center, University of Washington, Seattle, Washington 98108 [M. L.]

Bryostatin 1 is a natural antineoplastic agent that activates protein kinase C. Treatment of U937 human leukemic cells with bryostatin 1 caused a 60% reduction in cell growth, whereas another protein kinase C activator, phorbol myristate acetate (PMA), completely inhibited U937 cell growth. Both bryostatin 1 and PMA induced inhibition of cyclindependent kinase 2 (cdk2) activity. The first phase of cdk2 inhibition correlated with the transient induction of p21, a known inhibitor of cdk2. In contrast, the second phase of cdk2 inhibition correlated with the dephosphorylation of cdk2 on threonine-160, which must be phosphorylated for cdk2 activity. The level of growth inhibition induced by these two compounds correlated with the degree of cdk2 dephosphorylation as follows: bryostatin 1, 60%; PMA, 100%.

¹ This work was supported by NIH CA 42533 and ACS grant DHP 83 to ASK, CA45672 and a grant from the Veterans Administration Research Program to ML, and ACS grant IRG-66-32 to JB.

² To whom requests for reprints should be addressed, at Division of Hematology/Oncology, University of Alabama/Birmingham, 558T Lurleen B. Wallace Tumor Institute, 1824 Sixth Avenue South, Birmingham, AL 35294-3300.

Received 6/27/95. Accepted 7/20/95.

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