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Protein kinase Cε interacts with Stat3 and regulates its activation that is essential for the development of skin cancer
Author(s) -
Aziz Moammir H.,
Manoharan Herbert T.,
Sand Jordan M.,
Verma Ajit K.
Publication year - 2007
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20356
Subject(s) - protein kinase c , biology , phosphorylation , kinase , microbiology and biotechnology , signal transduction , bryostatin 1 , pkc alpha
Abstract Protein kinase C (PKC) represents a large family of phosphatidylserine (PS)‐dependent serine/threonine protein kinases. At least six PKC isoforms (α, δ, ε, η, µ, and ζ) are expressed in epidermis. PKC is a major intracellular receptor for 12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA) and is also activated by a variety of stress factors including ultraviolet radiation (UVR). PKC isozymes (α, δ, ε, and η), exhibit specificities to the development of skin cancer. PKCε, a calcium‐insensitive PKC isoform, is linked to the development of squamous cell carcinoma (SCC) elicited either by the 7,12‐Dimethylbenzanthracene (DMBA)‐TPA protocol or by repeated exposures to UVR. PKCε overexpressing transgenic mice, when treated either with TPA or exposed to UVR, elicit similar responses such as inhibition of apoptosis, promotion of cell survival, and development of SCC. PKCε overexpression increases Stat3 activation after either TPA treatment or UVR exposure. Both PKCε and signal transducers and activators of transcription‐3 (Stat3) are implicated in the development of SCC. However, the link between PKCε and Stat3 remains elusive. We found that PKCε interacts with Stat3. PKCε interaction with Stat3 was dependent upon UVR treatment. In reciprocal immunoprecipitation/blotting experiments, Stat3 coimmunoprecipitated with PKCε. Colocalization of PKCε with Stat3 was confirmed by double immunofluorescence staining. PKCε interaction with Stat3 was PKCε isoform specific and was not observed with other protein kinases. As observed in vitro with immunocomplex kinase assay with immunopurified PKCε and Stat3, PKCε phosphorylated Stat3 at the serine 727 residue. PKCε depletion prevented Stat3Ser727 phosphorylation, Stat3 DNA binding, and transcriptional activity. The results presented indicate that PKCε mediates Stat3 activation. © 2007 Wiley‐Liss, Inc.