Cell cycle regulatory effects of retinoic Acid and forskolin are mediated by the cyclin C gene.
As a partner of cyclin-dependent kinase (CDK) 3, Cyclin C controls cellular proliferation and, together with CDK8, represses gene transcription. In this study, we showed that the highly expressed Cyclin C gene is a direct target of the nuclear hormone all-trans retinoic acid (RA) in HEK293 human embryonal kidney cells. The RA receptor (RAR) gamma associates with a Cyclin C promoter region containing two RAR binding sites. The Cyclin C gene also directly responds to the cAMP activator Forskolin via the transcription factor CREB1 (cAMP response element-binding protein 1), for which we identified four binding sites within the first 2250 bp of its promoter. RARgamma and CREB1 show functional convergence via the corepressor NCoR1, which controls in particular the Forskolin response of Cyclin C. The histone deacetylases 1, 5, 6, 7 and 11 are involved in the basal expression of Cyclin C, but in HEK293 and MCF-7 human breast carcinoma cells the antiproliferative effects of the histone deacetylase inhibitor SAHA (suberoylanilide hydroxamic acid) are not mediated by Cyclin C. However, cell cycle progressing effects of all-trans RA and Forskolin are dependent on Cyclin C expression levels. This suggests that the primary regulation of Cyclin C by all-trans RA and Forskolin mediates some of the cell cycle control actions of these compounds.
Makkonen
Katri M
KM
Department of Biosciences, University of Kuopio, Finland.
Malinen
Marjo
M
Ropponen
Antti
A
Väisänen
Sami
S
Carlberg
Carsten
C
D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005576:Colforsin / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D056745:Cyclin C; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D056971:Nuclear Receptor Co-Repressor 1; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*; D000077337:Vorinostat; D000097768:Retinoic Acid Receptor gamma
D000970:Antineoplastic Agents; D005576:Colforsin; D017362:Cyclic AMP Response Element-Binding Protein; D056745:Cyclin C; D016213:Cyclins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014212:Tretinoin; D000077337:Vorinostat; D000097768:Retinoic Acid Receptor gamma; C503674:CCNC protein, human; C115163:CREB1 protein, human; C539127:NCOR1 protein, human