Protein Kinase Cε, which Sensitizes Skin to Sun's UV Radiation–Induced Cutaneous Damage and Development of Squamous Cell Carcinomas, Associates with Stat3

Abstract

Chronic exposure to UV radiation (UVR) is the major etiologic factor in the development of human skin cancers including squamous cell carcinoma (SCC). We have shown that protein kinase CE (PKCE), a Ca 2+ -independent, phospholipiddependent serine/threonine kinase, is an endogenous photosensitizer. PKCE is among the six isoforms (A, D, E, H, M, and Z) expressed in both mouse and human skin. PKCE transgenic mice, which overexpress PKCE in the basal epidermal cells and cells of the hair follicle, are highly sensitive to UVR-induced cutaneous damage and development of SCC. We now present that PKCE-overexpressing, but not PKCD-overexpressing, transgenic mice, when exposed to a single (4 kJ/m 2 ) or repeated ( four doses, 2 kJ/m 2 /dose, thrice weekly) UVR, emitted by Kodacel-filtered FS-40 sun lamps, elicit constitutive phosphorylation of signal transducers and activators of transcription 3 (Stat3) at both Tyr705 and Ser727 residues. UVR-induced phosphorylation of Stat3 accompanied increased expression of Stat3-regulated genes (c-myc, cyclin D1, cdc25A, and COX-2). In reciprocal immunoprecipitation/ blotting experiments, phosphorylated Stat3 coimmunoprecipitated with PKCE. As observed in vivo using PKCE knockout mice and in vitro in an immunocomplex kinase assay, PKCE phosphorylated Stat3 at Ser727 residue. These results indicate for the first time that (a) PKCE is a Stat3Ser727 kinase; (b) PKCE-mediated phosphorylation of StatSer727 may be essential for transcriptional activity of Stat3; and (c) UVR-induced phosphorylation of Ser727 may be a key component of the mechanism by which PKCE imparts sensitivity to UVR-induced development of SCC. [Cancer Res 2007;67(3):1385-94]

Preconditioning Mediated by Sublethal Oxygen—Glucose Deprivation-Induced Cyclooxygenase-2 Expression via the Signal Transducers and Activators of Transcription 3 Phosphorylation

“…However, our data were unable to characterize the direct interaction of ERK1/2 with STAT3 ( Figure 6). Next, we suggested that ePKC could directly phosphorylate STAT3 at the serine residue in neurons, as a direct interaction between ePKC and STAT3 phosphorylation at serine 727 residue has been shown in cancer cells (Aziz et al, 2007). However, we could not detect the direct interaction of ePKC with STAT3 ( Figure 6).…”

“…The STAT3-specific inhibitor used in this study was the SH 2 domain-binding peptide, which interferes with phosphorylation of the tyrosine residue, and disrupts STAT3 dimerization and STAT3 activity in vitro (Turkson et al, 2001). As mentioned earlier, complete activation of STAT3 requires phosphorylation at both tyrosine and serine residues (Aziz et al, 2007;Li and Shaw, 2004). In this context, these results led us to conjecture that the STAT3 inhibitory peptide prevented the complete activation process of STAT3 transcriptional activity and then inhibited STAT3-mediated COX-2 expression after PC.…”

“…In general, the transcriptional activity of the STATs involves their dimerization, nuclear translocation, DNA binding, and recruitment of transcriptional coactivators (Klampfer, 2006;Vinkemeier, 2004). The process of dimerization requires phosphorylation of STAT at tyrosine 705 residue by the Janus kinases and an additional phosphorylation at serine 727 residue by members of the MAP kinase family for complete activation (Aziz et al, 2007;Darnell, 1997;Li and Shaw, 2004). The dimerized STAT then undergoes nuclear translocation (Klampfer, 2006;Vinkemeier, 2004).…”

The PKC inhibitor AEB071 may be a therapeutic option for psoriasis

“…PKC isoforms expressed in keratinocytes may contribute to these changes. STAT3 has been shown to be phosphorylated at Ser727 residues by PKCε, and PKCε transgenic mice demonstrate phosphorylation of both Ser727 and Tyr705 residues and therefore display fully activated STAT3 (41). Keratinocyte-specific overexpression of PKCα in mice results in expression of TNF-α and VEGF and epidermal neutrophilic inflammation (42,43), i.e., characteristic features of psoriasis.…”

PKC and Cancer: Time for a Comeback?

“…Transgenic overexpression of PKCe in the skin drives the development of squamous cell carcinoma and a metastatic phenotype, and it predisposes mice to skin cancer in response to UVR exposure (11,12). There is a significant reduction of prostate cancer growth in TRAMP mice with PKCe-deficient background (13).…”