Following the administration of dibutyryl cAMP (dbcAMP), certain animal tumors cease growing or regress, suggesting that cAMP may inhibit tumor growth. Other histologically similar tumors are unresponsive. It has been suggested that in the resistant tumors there is a decrease in the capacity of the intracellular receptors to bind cAMP. Consistent with this hypothesis, a dbcAMP-resistant variant of the Morris hepatoma has been found to have less capacity to bind cAMP than do Morris hepatoma variants that are inhibited by dbcAMP. It is possible that in certain tumors unregulated cell replication is due in part to failure of inhibition of cell growth by endogenous cAMP due to impairment of intracellular cAMP binding. We postulate that in the dbcAMP-resistant tumors the impairment in binding may be severe, while in the dbcAMP responsive tumors there may be only a partial impairment in binding with the result that relatively large amounts of exogenous dbcAMP can inhibit growth. We have examined the cAMP binding proteins in the nuclei and cytoplasm of normal rat liver and have observed that cAMP binding in the nucleus and cytosol is enhanced by GTP and decreased by 5'AMP. We have also performed preliminary studies on the cytosol and nuclei from a dbcAMP responsive and non-responsive hepatomas and have observed differences in the effect of these nucleotides on nuclear cAMP binding when compared to normal liver. In the first part of this project, we plan to do further studies on normal liver to elucidate the mechanisms by which GTP enhances and 5'AMP inhibits the binding of cAMP to the individual nuclear and cytosolic binding proteins. Studies will also be done to investigate whether the hepatic cAMP binding proteins that are affected by GTP and 5'AMP are regulatory subunits of protein kinases and whether GTP and 5'AMP, by affecting cAMP binding, affect cAMP regulation of protein kinase activity. In addition, we will pursue further our recent finding that there is a cytosolic factor that mediates the enhancing effect of GTP on cAMP binding in the nucleus and cytosol and that can be separated from the cAMP binding proteins. In the second part of the project, we intend to study cAMP binding to the individual cAMP binding proteins in the nuclei and cytosol of a number of dbcAMP-responsive and nonresponsive hepatomas in the presence and absence of GTP and 5'AMP. If we observe abnormalities in the effects of GTP or 5'AMP on cAMP binding in these tumors, we will attempt to delineate the cause of these abnormalities. (K)
| Rosenberg, E M; Goodman, A D; Lipinski, T L (1989) Evidence for the existence of a GTP-dependent factor in hepatic cytosol that stimulates cyclic AMP binding: possible role in the modulation of cyclic AMP action. Metabolism 38:916-20 |
| Rosenberg, E M; Goodman, A D; Lipinski, T I (1987) Effects of fasting, feeding, and insulin on enhancing effect of GTP on cAMP binding in rat hepatic cytosol. Diabetes 36:37-42 |
