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Molecular and Cellular Biology, August 2004, p. 7298-7311, Vol. 24, No. 16
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.16.7298-7311.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Protein Kinase C Blocks Immediate-Early Gene Expression in Senescent Cells by Inactivating Serum Response Factor

Department of Biochemistry and Molecular Biology, Southern Alberta Cancer Centre, University of Calgary, Calgary, Alberta, Canada

Received 15 April 2003/ Returned for modification 13 June 2003/ Accepted 13 May 2004

Fibroblasts lose the ability to replicate in response to growth factors and become unable to express growth-associated immediate-early genes, including c-fos and egr-1, as they become senescent. The serum response factor (SRF), a major transcriptional activator of immediate-early gene promoters, loses the ability to bind to the serum response element (SRE) and becomes hyperphosphorylated in senescent cells. We identify protein kinase C delta (PKC) as the kinase responsible for inactivation of SRF both in vitro and endogenously in senescent cells. This is due to a higher level of PKC activity as cells age, production of the PKC catalytic fragment, and its nuclear localization in senescent but not in low-passage-number cells. The phosphorylation of T160 of SRF by PKC in vitro and in vivo led to loss of SRF DNA binding activity. Both the PKC inhibitor rottlerin and ectopic expression of a dominant negative form of PKC independently restored SRE-dependent transcription and immediate-early gene expression in senescent cells. Modulation of PKC activity in vivo with rottlerin or bistratene A altered senescent- and young-cell morphology, respectively. These observations support the idea that the coordinate transcriptional inhibition of several growth-associated genes by PKC contributes to the senescent phenotype.

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