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Molecular and Cellular Biology, September 2004, p. 8167-8183, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.8167-8183.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Protein Kinase C{delta} Regulates Keratinocyte Death and Survival by Regulating Activity and Subcellular Localization of a p38{delta}-Extracellular Signal-Regulated Kinase 1/2 Complex

Tatiana Efimova,1 Ann-Marie Broome,1 and Richard L. Eckert1,2,3,4,5*

Departments of Physiology and Biophysics,1 Dermatology,2 Oncology,3 Biochemistry,4 Reproductive Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio5

Received 16 April 2004/ Returned for modification 13 May 2004/ Accepted 9 June 2004

Protein kinase C{delta} (PKC{delta}) is an important regulator of apoptosis in epidermal keratinocytes. However, little information is available regarding the downstream kinases that mediate PKC{delta}-dependent keratinocyte death. This study implicates p38{delta} mitogen-activated protein kinase (MAPK) as a downstream carrier of the PKC{delta}-dependent death signal. We show that coexpression of PKC{delta} with p38{delta} produces profound apoptosis-like morphological changes. These morphological changes are associated with increased sub-G1 cell population, cytochrome c release, loss of mitochondrial membrane potential, caspase activation, and PARP cleavage. This death response is specific for the combination of PKC{delta} and p38{delta} and is not produced by replacing PKC{delta} with PKC{alpha} or p38{delta} with p38{alpha}. A constitutively active form of MEK6, an upstream activator of p38{delta}, can also produce cell death when coupled with p38{delta}. In addition, concurrent p38{delta} activation and extracellular signal-regulated kinase 1/2 (ERK1/2) inactivation are required for apoptosis. Regarding this inverse regulation, we describe a p38{delta}-ERK1/2 complex that may coordinate these changes in activity. We further show that this p38{delta}-ERK1/2 complex relocates into the nucleus in response to PKC{delta} expression. This regulation appears to be physiological, since H2O2, a known inducer of keratinocyte apoptosis, promotes identical PKC{delta} and p38{delta}-ERK1/2 activity changes, leading to similar morphological changes.

* Corresponding author. Mailing address: Department of Physiology and Biophysics, Rm. E532, Case Western Reserve University School of Medicine, 2109 Adelbert Rd., Cleveland, OH 44106-4970. Phone: (216) 368-5530. Fax: (216) 368-5586. E-mail: rle2{at}po.cwru.edu.

Molecular and Cellular Biology, September 2004, p. 8167-8183, Vol. 24, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.18.8167-8183.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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