title: Transcriptional and post-transcriptional down-regulation of cyclin D1 contributes to C6 glioma cell differentiation induced by forskolin.
abstract: Malignant gliomas are the most common and lethal intracranial tumors, and differentiation therapy shows great potential to be a promising candidate for their treatment. Here, we have elaborated that a PKA activator, forskolin, represses cell growth via cell cycle arrest in the G0/G1 phase and induces cell differentiation characteristic with elongated processes and restoration of GFAP expression. In mechanisms, we verified that forskolin significantly diminishes the mRNA and protein level of a key cell cycle regulator cyclin D1, and maintenance of low cyclin D1 expression level was required for forskolin-induced proliferation inhibition and differentiation by gain and loss of function approaches. In addition, that forskolin down-regulated the cyclin D1 by proteolytic (post-transcriptional) mechanisms was dependent on GSK-3β activation at Ser9. The pro-differentiation activity of forskolin and related molecular mechanisms imply that forskolin can be developed into a candidate for the future in differentiation therapy of glioma, and cyclin D1 is a promising target for pro-differentiation strategy.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, P R China.
authors.forename: Songmin
authors.initials: S
authors.lastname: He
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhu
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yijun
authors.initials: Y
authors.lastname: Huang
authors.forename: Yanqiu
authors.initials: Y
authors.lastname: Ou
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Guangmei
authors.initials: G
authors.lastname: Yan
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology*; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D020536:Enzyme Activators / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005910:Glioma; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D010766:Phosphorylation; D059748:Proteolysis; D051381:Rats; D014158:Transcription, Genetic
chemical_list: C530106:Ccnd1 protein, rat; D020536:Enzyme Activators; D019938:Cyclin D1; D005576:Colforsin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3