Ei24-deficiency attenuates protein kinase Cα signaling and skin carcinogenesis in mice.

Etoposide-induced gene 24 (Ei24) is a p53 target gene that inhibits growth, induces apoptosis and autophagy, as well as suppresses breast cancer. To evaluate the role of Ei24 in in vivo tumorigenesis, we generated an Ei24-deficient mouse model. Here, we report that, although Ei24 homozygous knockout mice are embryonic lethal, Ei24 heterozygous null mice are attenuated to DMBA/TPA-induced carcinogenesis with regard to the number and size of tumors but not the incidence. Ei24 contains a functional consensus motif, named as an R motif that is highly analogous to amino acids 105-110 of RINCK1, an E3 ligase for protein kinase C (PKC) proteins. We found that Ei24 stabilizes PKCαvia RINCK degradation and competition with RINCK for binding with the C1a domain of PKCα. We also found that Ei24 contributes to PKCα-mediated transactivation of EGFR by promoting PKCα membrane localization and interaction with EGFR. Finally, using Oncomine database we show that Ei24 and EGFR are upregulated in some subsets of human HNSCC. These results suggest that Ei24 is a regulator of the RINCK1-PKCα-EGFR signaling pathway in the development of skin-cancer.