Abstract
The functional properties of four diacylglycerol (DAG) analogues were compared using cell-signaling assays based on the protein RasGRP1, a DAG-regulated Ras activator. Compounds 1 and 2, synthetic analogues of bryostatin 1, were compared to authentic bryostatin 1 and phorbol 12-myristate-13-acetate (PMA). The two "bryologues" were able to activate RasGRP1 signaling rapidly in cultured cells and isolated mouse thymocytes. They elicited expression of the T cell activation marker CD69 in human T cells. DAG analogues promptly recruited RasGRP1 to cell membranes, but they did not induce RasGRP1 proteolysis. Bryostatin 1 and compounds 1 and 2 appeared to be less potent than PMA at inducing aggregation of mouse thymocytes, a PKC-dependent, RasGRP1-independent response. In addition to sharing potential anticancer properties with bryostatin 1, compounds 1 and 2 might be clinically useful as modulators of the immune system.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, CD / biosynthesis
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Antigens, Differentiation, T-Lymphocyte / biosynthesis
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Bryostatins
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Cell Aggregation / drug effects
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Cell Membrane / metabolism
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / physiology*
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Humans
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Immunologic Factors / chemical synthesis*
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Immunologic Factors / chemistry
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Immunologic Factors / pharmacology
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Lactones / chemical synthesis*
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Lactones / chemistry
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Lactones / pharmacology
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Lectins, C-Type
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Macrolides
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Mice
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Mutation
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Phosphorylation
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Protein Kinase C / physiology
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Protein Transport / drug effects
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Signal Transduction / drug effects
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism
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T-Lymphocytes / physiology
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Tetradecanoylphorbol Acetate / pharmacology
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Thymus Gland / cytology
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Transfection
Substances
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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Bryostatins
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CD69 antigen
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DNA-Binding Proteins
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Guanine Nucleotide Exchange Factors
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Immunologic Factors
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Lactones
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Lectins, C-Type
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Macrolides
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RASGRP1 protein, human
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Rasgrp1 protein, mouse
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bryostatin 1
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Protein Kinase C
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Extracellular Signal-Regulated MAP Kinases
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Tetradecanoylphorbol Acetate