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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{delta} Blocks Immediate-Early Gene Expression in Senescent Cells by Inactivating Serum Response Factor

Keith Wheaton and Karl Riabowol*

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{delta}) 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{delta} activity as cells age, production of the PKC{delta} catalytic fragment, and its nuclear localization in senescent but not in low-passage-number cells. The phosphorylation of T160 of SRF by PKC{delta} in vitro and in vivo led to loss of SRF DNA binding activity. Both the PKC{delta} inhibitor rottlerin and ectopic expression of a dominant negative form of PKC{delta} independently restored SRE-dependent transcription and immediate-early gene expression in senescent cells. Modulation of PKC{delta} 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{delta} contributes to the senescent phenotype.

* Corresponding author. Mailing address: #370 Heritage Medical Research Building, 3330 Hospital Dr., Calgary, Alberta T2N 4N1, Canada. Phone: (403) 220-8695. Fax: (403) 270-0834. E-mail: karl{at}ucalgary.ca.

Molecular and Cellular Biology, August 2004, p. 7298-7311, Vol. 24, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.16.7298-7311.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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