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Alterations in Cyclic Adenosine 3':5'-Monophosphate-dependent Protein Kinases during Normal and Neoplastic Lung Development¹

School of Pharmacy, University of Colorado, Boulder, Colorado 80309

The regulatory molecule, cyclic adenosine 3':5'-monophosphate (cAMP), can inhibit cell proliferation, reverse the neoplastic phenotype, and promote tumor regression. Since the biological effects of cAMP are mediated by an activation of protein kinase enzymes, the interaction of cAMP with the regulatory subunits of type I and II isozymes (R_I and R_II) was studied in normal and neoplastic tissues. Regulatory subunits in extracts from normal adult and neonatal lung, urethan-induced lung adenoma, and uninvolved lung tissue were covalently labeled with 8-azidoadenosine cyclic 3':5'-[³²P]monophosphate (8-N₃-[³²P]cAMP), a specific photoaffinity analog of cAMP. The ability of R_I to bind 8-N₃-[³²P]cAMP is the same in all tissues, while R_II binding characteristics depend on both developmental stage and neoplastic state. Binding curves for R_II from normal adult lung suggest two 8-N₃-[³²P]cAMP binding sites, one which saturates at 125 nM and one which saturates at 800 nM. The R_II from tumor tissue appears to have only the low-affinity site, while R_II from neonatal lung shows greatly reduced binding to both sites. These changes in 8-N₃-[³²P]-cAMP binding characteristics correlated with changes in the cAMP dependence of R_II autophosphorylation. In adult lung, cAMP can either stimulate or inhibit endogenous phosphorylation of R_II, depending on the divalent cation (Mg²⁺ or Zn²⁺, respectively) present during the reaction. In the tumor, cAMP has little stimulatory effect but is strongly inhibitory. The amount of ³²P that can be incorporated into neonatal R_II is very slight with either cation. Thus, both the 8-N₃-[³²P]cAMP binding sites on R_II and the phosphorylatable sites on R_II change during normal and neoplastic development. Tumor growth is unregulated by normal physiological constraints. A decreased responsiveness to alterations in intracellular cAMP concentrations in lung adenomas may increase the proliferative rate and help maintain the neoplastic state.

¹ Supported by USPHS Grants ES02370 and RR 09065 and by the Colorado Heart Association.

² To whom requests for reprints should be addressed.

Received 9/29/80. Accepted 12/16/80.

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