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Molecular and Cellular Biology, July 2000, p. 4580-4590, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Involvement of p21Waf1/Cip1 in Protein Kinase C Alpha-Induced Cell Cycle Progression

Arnaud Besson and V. Wee Yong*

Departments of Oncology and Clinical Neurosciences, University of Calgary, Calgary, Canada

Received 14 February 2000/Accepted 15 March 2000

Protein kinase C (PKC) plays an important role in the regulation of glioma growth; however, the identity of the specific isoform and mechanism by which PKC fulfills this function remain unknown. In this study, we demonstrate that PKC activation in glioma cells increased their progression through the cell cycle. Of the six PKC isoforms that were present in glioma cells, PKC alpha  was both necessary and sufficient to promote cell cycle progression when stimulated with phorbol 12-myristate 13-acetate. Also, decreased PKC alpha  expression resulted in a marked decrease in cell proliferation. The only cell cycle-regulatory molecule whose expression was rapidly altered and increased by PKC alpha  activity was the cyclin-cyclin-dependent kinase (CDK) inhibitor p21Waf1/Cip1. Coimmunoprecipitation studies revealed that p21Waf1/Cip1 upregulation was accompanied by an incorporation of p21Waf1/Cip1 into various cyclin-CDK complexes and that the kinase activity of these complexes was increased, thus resulting in cell cycle progression. Furthermore, depletion of p21Waf1/Cip1 by antisense strategy attenuated the PKC-induced cell cycle progression. These results suggest that PKC alpha  activity controls glioma cell cycle progression through the upregulation of p21Waf1/Cip1, which facilitates active cyclin-CDK complex formation.

* Corresponding author. Mailing address: University of Calgary, 3330 Hospital Dr., NW, Calgary, Alberta T2N 4N1, Canada. Phone: (403) 220-3544. Fax: (403) 283-8731. E-mail: vyong{at}acs.ucalgary.ca.

Molecular and Cellular Biology, July 2000, p. 4580-4590, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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