Inactivation of DNA-Dependent Protein Kinase by Protein Kinase Cdelta : Implications for Apoptosis

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Molecular and Cellular Biology, November 1998, p. 6719-6728, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Inactivation of DNA-Dependent Protein Kinase by Protein Kinase C $delta$ : Implications for Apoptosis

Ajit Bharti,¹ Stine-Kathrein Kraeft,² Mrinal Gounder,¹ Pramod Pandey,¹ Shengfang Jin,³ Zhi-Min Yuan,¹ Susan P. Lees-Miller,⁴ Ralph Weichselbaum,⁵ David Weaver,³ Lan Bo Chen,² Donald Kufe,¹ and Surender Kharbanda¹^,^*

Cancer Pharmacology¹ and Cancer Biology,² Dana-Farber Cancer Institute, and Department of Microbiology and Molecular Genetics,³ Harvard Medical School, Boston, Massachusetts 02115; Department of Biological Sciences University of Calgary, Calgary, Alberta, Canada T2N IN4⁴; and Department of Radiation and Cellular Oncology University of Chicago, Chicago, Illinois 60637⁵

Received 6 April 1998/Returned for modification 2 June 1998/Accepted 28 July 1998

Protein kinase C $delta$ (PKC $delta$ ) is proteolytically cleaved and activated at the onset of apoptosis induced by DNA-damaging agents,tumor necrosis factor, and anti-Fas antibody. A role for PKC $delta$ in apoptosis is supported by the finding that overexpression ofthe catalytic fragment of PKC $delta$ (PKC $delta$ CF) in cells is associatedwith the appearance of certain characteristics of apoptosis. However,the functional relationship between PKC $delta$ cleavage and inductionof apoptosis is unknown. The present studies demonstrate thatPKC $delta$ associates constitutively with the DNA-dependent proteinkinase catalytic subunit (DNA-PKcs). The results show that PKC $delta$ CF phosphorylates DNA-PKcs in vitro. Interaction of DNA-PKcs withPKC $delta$ CF inhibits the function of DNA-PKcs to form complexes withDNA and to phosphorylate its downstream target, p53. The resultsalso demonstrate that cells deficient in DNA-PK are resistantto apoptosis induced by overexpressing PKC $delta$ CF. These findingssupport the hypothesis that functional interactions between PKC $delta$ and DNA-PK contribute to DNA damage-induced apoptosis.

^* Corresponding author. Mailing address: Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, 44 BinneySt., Boston, MA 02115. Phone: (617) 632-2938. Fax: (617) 632-2934.E-mail: Surender_Kharbanda{at}MacMailGW.dfci.harvard.edu.

Molecular and Cellular Biology, November 1998, p. 6719-6728, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

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Inactivation of DNA-Dependent Protein Kinase by Protein Kinase C: Implications for Apoptosis

Inactivation of DNA-Dependent Protein Kinase by Protein Kinase C $delta$ : Implications for Apoptosis