Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 112, Issue 9, Pages 2241-2249Publisher
WILEY
DOI: 10.1002/jcb.23140
Keywords
CYCLIN D1; GSK-3 beta; GLIOMA; FORSKOLIN; DIFFERENTIATION; CELL CYCLE
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Funding
- National Natural Science Foundation of China [30830111, 30801408]
- National Natural Science Foundation of Guangdong Province [8451008901000297]
- Chinese Postdoctoral Science [20100480824]
- Guangzhou Scientific and Technological Programs [2008Z1-E561]
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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-3 beta 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. J. Cell. Biochem. 112: 2241-2249, 2011. (C) 2011 Wiley-Liss, Inc.
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