title: Synthetic bryostatin analogues activate the RasGRP1 signaling pathway.
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.
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. jim.stone@ualberta.ca
authors.forename: James C
authors.initials: JC
authors.lastname: Stone
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Stang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zheng
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Dower
authors.forename: Stacey E
authors.initials: SE
authors.lastname: Brenner
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Baryza
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wender
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D054713:Bryostatins; D002449:Cell Aggregation / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D037181:Lectins, C-Type; D018942:Macrolides; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology; D014162:Transfection; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D054713:Bryostatins; D004268:DNA-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D020662:Guanine Nucleotide Exchange Factors; D007155:Immunologic Factors; D007783:Lactones; D037181:Lectins, C-Type; D018942:Macrolides; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D000099192:CD69 Antigens; C491790:RASGRP1 protein, human; C112278:Rasgrp1 protein, mouse; C046785:bryostatin 1