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

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

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