Possible mechanism of phorbol diester-induced maturation of human promyelocytic leukemia cells.
Open Access
- 1 February 1984
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 73 (2), 448-457
- https://doi.org/10.1172/jci111231
Abstract
The phorbol diesters are the most potent inducers of differentiation of the promyelocytic leukemia cell line, HL-60. Soluble phorbol diester receptors from HL-60 cells were obtained from the cytosolic fraction and from the particulate fraction by either divalent ion chelation or detergent extraction. The partially purified soluble phorbol diester receptors required exogenous Ca2+ and phospholipid for maximal binding and displayed a dissociation constant (KD) of 8.1 nM for [3H]phorbol 12,13-dibutyrate. Phorbol diester analogues inhibited [3H]phorbol 12,13-dibutyrate binding in a stereospecific manner consistent with their biologic potency. The soluble phorbol diester receptors prepared by all three methods copurified in a constant ratio with the Ca2+/phospholipid-dependent protein kinase C through ammonium sulfate precipitation, DEAE ion exchange, and gel filtration chromatography. Partially purified protein kinase C was directly activated by the phorbol diesters even in the absence of exogenous Ca2+. The ability of a series of phorbol analogues to activate the kinase correlated with their known activity as inducers of cell differentiation. In addition, phorbol diester stimulation altered the phosphate acceptor substrate profile of protein kinase C, at least in part, by alteration of the Michaelis constant (Km). These data suggest that protein kinase C is the phorbol diester receptor and that phorbol diester-induced macrophage maturation of HL-60 cells may be mediated by activation of intracellular protein kinase C.This publication has 63 references indexed in Scilit:
- Abelson murine leukaemia virus protein is phosphorylated in vitro to form phosphotyrosineNature, 1980
- DIFFERENTIATION OF HUMAN LEUKEMIAS IN RESPONSE TO 12-0-TETRADECANOYLPHORBOL-13-ACETATE INVITRO1980
- Specific binding of phorbol ester tumor promotersProceedings of the National Academy of Sciences, 1980
- Human promyelocytic leukemia cells in culture differentiate into macrophage-like cells when treated with a phorbol diester.Proceedings of the National Academy of Sciences, 1979
- Induction of Differentiation in Human Promyelocytic Leukemia Cells by Tumor PromotersScience, 1979
- Induction of terminal differentiation in human promyelocytic leukemia cells by tumor-promoting agents.Proceedings of the National Academy of Sciences, 1979
- CHARACTERIZATION OF THE CONTINUOUS, DIFFERENTIATING MYELOID CELL-LINE (HL-60) FROM A PATIENT WITH ACUTE PROMYELOCYTIC LEUKEMIA1979
- Continuous growth and differentiation of human myeloid leukaemic cells in suspension cultureNature, 1977
- A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye BindingAnalytical Biochemistry, 1976
- A speculative review; the probable nature of promoting action and its significance in the understanding of the mechanism of carcinogenesis.1954