Positioning Atypical Protein Kinase C Isoforms in the UV-Induced Apoptotic Signaling Cascade

Abstract

Recent studies have documented the involvement of the atypical protein kinase C (aPKC) isoforms in important cellular functions such as cell proliferation and survival. Exposure of cells to a genotoxic stimulus that induces apoptosis, such as UV irradiation, leads to a profound inhibition of the atypical PKC activity in vivo. In this study, we addressed the relationship between this phenomenon and different proteins involved in the apoptotic response. We show that (i) the inhibition of the aPKC activity precedes UV-induced apoptosis; (ii) UV-induced aPKC inhibition and apoptosis are independent of p53; (iii) Bcl-2 proteins are potent modulators of aPKC activity; and (iv) the aPKCs are located upstream of the interleukin-converting enzymelike protease system, which is required for the induction of apoptosis by both Par-4 (a selective aPKC inhibitor) and UV irradiation. We also demonstrate here that inhibition of aPKC activity leads to a decrease in mitogen-activated protein (MAP) kinase activity and simultaneously an increase in p38 activity. Both effects are critical for the induction of apoptosis in response to Par-4 expression and UV irradiation. Collectively, these results clarify the position of the aPKCs in the UV-induced apoptotic pathway and strongly suggest that MAP kinases play a role in this signaling cascade.

Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine

“…Deprivation of neurotrophic factors or UV irradiation not only activates stress kinase cascades but also leads to dramatic inhibition of the ERK pathway (13). Furthermore, ERK expression in NIH 3T3 cells impairs the majority of the UV-induced apoptotic response (14). The prosurvival function of ERK was confirmed in a recent report showing that inhibition of ERK signaling leads to increased sensitivity to cisplatin (cis-diammine-dichloroplatinum) in ovarian cancer cells (31).…”

“…In addition, ERK is required for survival signaling in response to cellular growth factors (13). Furthermore, overexpression of ERK in NIH 3T3 cells largely impairs the UV-induced apoptotic response (14). Thus, it seems that the cell fate (i.e., death or survival) is decided by a critical balance between the ERK pathway and the JNK or p38 MAPK pathway.…”

Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis

“…This study showed that Par-4 speci®cally inhibits PKC isoforms x and l/i but not others, thereby interrupting signaling to AP1 and inducing apoptosis (Berra et al, 1997). It is conceivable that Par-4 interconnects di erent signaling pathways.…”

p38 kinase mediates nitric oxide-induced apoptosis of chondrocytes through the inhibition of protein kinase C ζ by blocking autophosphorylation

“…[15][16][17][18][19] The chondrocyte pro-and antiapoptotic functions of p38 kinase and PKCz, respectively, are also observed in other cell types. [21][22][23][24] Evidence that PKCz provides survival signals in chondrocytes is supported by the observations that ectopic expression of wild-type or constitutively active PKCz inhibited NO-induced apoptosis of articular chondrocytes, whereas inhibition of PKCz activity by PS-PKCz potentiated NO-induced apoptosis. 15 Currently, underlying molecular mechanism leading to the inhibition of p38 kinase-induced apoptosis of chondrocyte by PKCz is not known.…”