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Kinetics of Adenosine 3':5'-Monophosphate-dependent Protein Kinase Activation and Inhibition of Thymidine Incorporation into DNA in P1798 Lymphosarcoma Cells¹

Departments of Chemistry and Biochemistry, North Texas State University, and Texas College of Osteopathic Medicine, Denton, Texas 76203

The kinetics for activation of the cyclic adenosine 3':5'-monophosphate (cyclic AMP)-dependent protein kinase (PKA) and thymidine incorporation into DNA was investigated in epinephrine- and prostaglandin E₁ (PGE₁)-treated murine P1798 lymphosarcoma cells. A positive correlation between the duration and extent of PKA activation and Accumulation of cyclic AMP and inhibition of thymidine incorporation into DNA was observed with both hormones. Epinephrine and PGE₁ elevated intracellular cyclic AMP 34- and 14-fold, respectively. All hormone concentrations which increased cyclic AMP accumulation also promoted inhibition of thymidine incorporation into DNA. In addition, dibutyryl cyclic AMP (50 µM) inhibited thymidine incorporation.

No difference in the kinetics for activation of PKA was observed when cells were treated with µM epinephrine or PGE₁. With both agents, 50% PKA activation was observed when intracellular cyclic AMP concentrations were elevated 6.5-fold, or to 9 pmol/10⁶ cells. In the presence of µM epinephrine, the cyclic AMP concentration was approximately 3-fold greater than that required for maximal PKA activation. In this case, the duration of the activation time for PKA was also 3- to 4-fold longer than that observed with 0.1 µM epinephrine.

The data are consistent with a mechanism wherein both epinephrine and PGE₁ suppress DNA synthesis by a cyclic AMP-mediated cascade of protein phosphorylation. No evidence for independent cyclic AMP or PKA pools which respond independently to either epinephrine or PGE₁ could be detected.

¹ Supported by the Robert A. Welch Foundation (Grant B 864) and the American Osteopathic Association (Grant 80-11-323).

² Present address: Department of Pharmacology, University of Texas Health Science Center, Dallas, Texas 75234.

³ To whom requests for reprints should be addressed.

Received 8/26/82. Accepted 4/21/83.