Protein Kinase Cε Inhibits UVR-Induced Expression of FADD, an Adaptor Protein, Linked to both Fas- and TNFR1-Mediated Apoptosis

Abstract

PKCε overexpression in FVB/N transgenic mice sensitized skin to ultraviolet radiation (UVR)-induced development of squamous cell carcinomas (SCC) (Wheeler et al., 2004; Wheeler et al., 2005) and suppressed formation of sunburn cells, which are DNA-damaged keratinocytes undergoing apoptosis (Wheeler et al., 2004). Here, we elucidated the mechanisms associated with inhibition of UVR-induced appearance of sunburn cells in PKCε transgenic mice. We found that the inhibition of UVR-induced sunburn cell formation in PKCε transgenic mice may be the result of the inhibition of the expression of Fas, Fas ligand (Fas-L) and the mammalian death adaptor protein termed Fas-associated with death domain (FADD). The adaptor protein FADD is the key component of the death inducing signaling complex of both Fas and tumor necrosis factor receptor 1 (TNF-R1). A decreased expression of epidermal FADD was observed after a single UVR exposure. However, a complete loss of FADD expression was found after four (Monday, Wednesday, Friday and Monday) repeated UVR exposures. FADD transmits apoptotic signals from death receptors to the downstream initiator caspase-8 and connects to the mitochondrial intrinsic apoptotic signal transduction pathway by the cleavage of Bid, a Bcl-2 family member. PKCε-mediated loss of FADD expression inhibited UVR signals to the activation of both extrinsic and intrinsic apoptotic pathways.

Light, including ultraviolet

“…It is important to understand that programmed cell death of UV-damaged skin cells is a definitive cancer-preventing pathway. Transgenic animals designed to be resistant to the development of UV-induced sunburn cells can tolerate more UV radiation without burning, but they are predisposed to developing skin cancers [5, 12]. …”

Use of a novel sonosensitizer in sonodynamic therapy of U251 glioma cells in vitro

“…Apoptosis is characterized by a number of well-defined features, including phosphatidyserine exposure, membrane blabbing, activation of caspase, chromatin condensation and DNA fragmentation (15). Classical apoptosis may proceed by the intrinsic and/or extrinsic pathway (16)(17)(18). In the intrinsic pathway, mitochondria are induced to release a number of factors, leading to the formation of the apoptosome, which is comprised of the adapter protein Apaf-1, cytochrome c and caspase-9 (19,20).…”

New insights into the characteristics of DRAK2 and its role in apoptosis: From molecular mechanisms to clinically applied potential

“…In addition, DAPK1 and DAPK2 show similarities in their regulation of kinase activity within the catalytic structural domain and both show the following two aspects: 1 ) upon Ser308 dephosphorylation, calcium-activated CaM binds to the self-regulated/CaM-bound fragment pulling the structural domain out of the catalytic cleft; 2 ) simultaneously, CaM binding promotes the dephosphorylation of Ser308 ( Shoval et al, 2011 ; Simon et al, 2016 ), and the dephosphorylated Ser308 increases the DAPK2 activity by promoting dimerization like the dephosphorylated Ser318; therefore, the binding of CaM and the dephosphorylation of Ser308 are reciprocal. In addition, a number of studies have confirmed this role of Ser308 in DAPK1 and DAPK2, replacing all Ser308 in both kinases with Ala or deleting the CaM-binding region in both kinases to produce constitutively active kinases that exhibit more potent killing and non-Ca-dependent catalytic activity ( Bialik and Kimchi, 2006 ; Aziz et al, 2009 ). In addition to an N-terminal catalytic domain that is 83% homologous to DAPK1, DAPK3 also has a nuclear localization signal (NLS) sequence and a leucine zipper domain at the C-terminus (427–441).…”