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Regulation of the Adenylate Cyclase System in Transplantable Hepatomas¹

Department of Obstetrics-Gynecology and Biochemistry, University of Florida Medical School, Gainesville, Florida 32610 [W. E. C.], and Department of Biochemistry, Howard University Medical School, Washington, D. C. 20059 [H. P. M.]

Adenylate cyclase systems were examined in purified membrane preparations from normal rat liver and several Morris hepatomas with differing growth rates. All tumor membrane preparations had lower relative specific activities than did liver preparations. Liver adenylate cyclase was stimulated by fluoride, glucagon and guanyl-5'-yl imidodiphosphate [Gpp(NH)p]. Membranes from two slow-growing hepatomas (hepatomas 20 and 21) contained adenylate cyclase activities which are also stimulated by each of these three modulators. Membrane adenylate cyclases from several fast-growing hepatomas (hepatomas 3924A, 7777, 5123tc, and 9618A₂) were marginally stimulated by glucagon but were readily stimulated by fluoride and Gpp(NH)p. Examination of the highly specific binding of ¹²⁵I-glucagon to the various membrane preparations revealed much less binding in all the tumor membranes than in liver membranes.

More detailed kinetic examination of membranes prepared from liver, slow-growing hepatoma 21 (which had reasonable binding to and stimulation by glucagon), and fast-growing hepatoma 3924A (which had marginal binding to and stimulation by glucagon) revealed major differences in rates of cyclic adenosine 3':5'-monophosphate production in the absence and presence of glucagon, Gpp(NH)p, and glucagon plus Gpp(NH)p and in the combined alteration of magnesium:adenosine 5'-triphosphate ratio and temperatures. The different kinetic characteristics in the hepatoma adenylate cyclase systems may be due to different structural characteristics of the tumor membranes or may be due to altered hormonal receptors, catalytic units, or receptor-catalytic unit interrelationships within the tumor membrane.

¹ This research was supported in part by USPHS Grants CA-11818, CA-10729, and CA-10906.

² Recipient of NIH Research Career Development Award CA-70187.

Received 10/ 2/75. Accepted 1/ 7/76.