| First Author | Tam HW | Year | 2019 |
| Journal | Carcinogenesis | PubMed ID | 30698678 |
| Mgi Jnum | J:288534 | Mgi Id | MGI:6416188 |
| Doi | 10.1093/carcin/bgz012 | Citation | Tam HW, et al. (2019) C/EBPbeta Suppresses Keratinocyte Autonomous Type 1 IFN Response and p53 to Increase Cell Survival and Susceptibility to UVB-induced Skin Cancer. Carcinogenesis 40(9):1099-1109 |
| abstractText | p53 is activated by DNA damage and oncogenic stimuli to regulate senescence, apoptosis and cell cycle arrest which are essential to prevent cancer. Here, we utilized UVB radiation, a potent inducer of DNA damage, p53, apoptosis and skin cancer to investigate the mechanism of C/EBPbeta in regulating p53-mediated apoptosis in keratinocytes and to test whether the deletion of C/EBPbeta in epidermis can protect mice from UVB-induced skin cancer. UVB-treatment of C/EBPbeta skin conditional knockout (CKObeta) mice increased p53 protein levels in epidermis and enhanced p53-dependent apoptotic activity 3-fold compared to UVB-treated control mice. UVB increased C/EBPbeta levels through a p53-dependent pathway and stimulated the formation of a C/EBPbeta-p53 protein complex; knockdown of C/EBPbeta increased p53 protein stability in keratinocytes. These results suggest a p53-C/EBPbeta feedback loop, whereby C/EBPbeta a transcriptional target of a p53 pathway, functions as a survival factor by negatively regulating p53 apoptotic activity in response to DNA damage. RNAseq analysis of UVB-treated CKObeta epidermis unexpectedly revealed that type 1 interferon (IFN) pathway was the most highly enriched pathway. Numerous proapoptotic ISGs were up-regulated including some known to enhance p53 apoptosis. Our results indicate that p53 and IFN pathways function together in response to DNA damage to result in the activation of extrinsic apoptosis pathways and caspase 8 cleavage. Lastly, we observed CKObeta mice were resistant to UVB-induced skin cancer. Our results suggest C/EBPbeta represses apoptosis through keratinocyte autonomous suppression of the type 1 IFN response and p53 to increase cell survival and susceptibility to UVB-induced skin cancer. |
