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Mimicry of Bryostatin 1 Induced Phosphorylation Patterns in HL-60 Cells by High Phorbol Ester Concentrations¹

Molecular Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892 [B. S. W., P. M. B.], and Cancer Research Institute and Department of Chemistry, Arizona State University, Tempe, Arizona 85287 [Y. K., G. R. P.]

The bryostatins are a group of macrocyclic lactones isolated from the marine bryozoan Bugula neritina. Bryostatin 1, like the phorbol esters, activates protein kinase C; however, it partially inhibits the phorbol ester induced differentiation of the human promyelocytic leukemic cell line HL-60. We compared the phosphorylation response in HL-60 cells treated with phorbol 12,13-dibutyrate or bryostatin 1. Bryostatin 1 enhanced the phosphorylation of the same proteins as did typical concentrations (10^-8-10^-9 M) of phorbol 12,13-dibutyrate. In addition, bryostatin 1 caused the appearance of 2 phosphorylated protein spots with molecular weights of 70,000 and pIs of 6.3–6.4. These latter phosphorylations were evident after a 30-min exposure to bryostatin 1 at 6 nM. Phorbol 12,13-dibutyrate concentrations of at least 600 nM, approximately 100-fold that necessary to induce differentiation, also induced the appearance of these phosphoprotein spots. The M_r 70,000 phosphoproteins were located in the ionic detergent-soluble cellular fraction which would contain the cytoskeletal proteins. Their phosphorylation was almost totally on serine residues. We speculate that phorbol esters at very high concentrations may more closely resemble bryostatin 1.

¹ B. S. W. was the recipient of a Leukemia Society of America Fellowship. The Arizona State University-Cancer Research Institute Laboratory received financial support from the Fannie E. Rippel Foundation, Dalton Endowment Fund, and USPHS Grants CA-16049-07 to -11 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed.

Received 2/19/88. Revised 7/22/88. Accepted 7/28/88.