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Antagonism of Concanavalin A Capping in Phorbol Ester-activated Lymphocytes by Calmodulin Inhibitors and Certain Amino Acid Esters¹

McArdle Laboratory for Cancer Research, The University of Wisconsin, Madison, Wisconsin 53706

12-O-Tetradecanoylphorbol-13-acetate (TPA), an effective tumor promoter in mouse skin and comitogen in bovine lymphocytes, rapidly stimulates concanavalin A-mediated cap formation in the latter cells. The ability of different phorbol derivatives to facilitate the capping reaction correlates well with their potencies as lymphocyte comitogens and as tumor-promoting agents. This effect of TPA on capping in bovine lymphocytes, which is apparent within min, is neither mimicked nor altered by dibutyryl cyclic adenosine 3':5'-monophosphate or cyclic guanosine 3':5'-monophosphate. Cytochalasin D, a microfilament-disrupting agent, inhibits cap formation, thereby suggesting the participation of microfilaments in the response. Benzoyl tyrosine ethyl ester selectively inhibits the TPA-stimulated cap formation, whereas benzoyl tyrosinamide is inactive. A comparison of related amino acid derivatives reveals that their activities are dependent on the nature of both the amino acid side chain and the carboxyl end blocking group. Trifluoperazine and N-(6-aminohexyl)-5-chloronaphthalenesulfonamide, known inhibitors of the calmodulin-dependent processes, also selectively block the TPA-stimulated cap formation, whereas trifluoperazine sulfoxide, a less effective calmodulin antagonist, is relatively inactive. These data suggest that the stimulation of capping by TPA involves the activation of a calmodulin-dependent process which may also be regulated by the function of an esterase.

¹ Financial support was provided by Grants CA-07175 and CA-23076 from the National Cancer Institute, USPHS, and NIH Training Grants CA-09020 and CA-09230.

² Recipient of Research Career Award CA-00685 from the National Cancer Institute. To whom requests for reprints should be addressed.

Received 11/ 6/81. Accepted 2/25/82.