Activation of adenylate cyclase by forskolin increases the protein stability of RCAN1 (DSCR1 or Adapt78).
Overexpression of Regulator of Calcineurin 1 (RCAN1/DSCR1/Adapt78) is known to inhibit the calcineurin-NFAT dependent signaling pathway. In this report, we find that activation of adenylate cyclase by forskolin increases the expression of RCAN1 through the increase of the protein's half-life. The ability of forskolin to increase the accumulation of RCAN1 protein is significantly inhibited with protein kinase A inhibitors such as KT5720 and H-89. Furthermore, forskolin targets the central and C-terminal region of RCAN1 and enhances the inhibitory effect of RCAN1 on the calcineurin-mediated activation of NFAT. Our findings provide the first evidence that the accumulation of the RCAN1 protein by cAMP acts as an important regulatory mechanism in the control of the calcineurin-dependent cellular pathway.
Seo
Su Ryeon
SR
Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701, Republic of Korea. suryeonseo@kangwon.ac.kr
Kim
Seon Sook
SS
Chung
Kwang Chul
KC
D000262:Adenylyl Cyclases / Q000096:biosynthesis*; D019703:Calcineurin / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D006207:Half-Life; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D009124:Muscle Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D002227:Carbazoles; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D009124:Muscle Proteins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C108612:RCAN1 protein, human; D013449:Sulfonamides; D005576:Colforsin; C057416:KT 5720; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D000262:Adenylyl Cyclases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide