| First Author | Jansen AP | Year | 2005 |
| Journal | Cancer Res | Volume | 65 |
| Issue | 14 | Pages | 6034-41 |
| PubMed ID | 16024603 | Mgi Jnum | J:100086 |
| Mgi Id | MGI:3586930 | Doi | 10.1158/0008-5472.CAN-04-2119 |
| Citation | Jansen AP, et al. (2005) Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis. Cancer Res 65(14):6034-41 |
| abstractText | Programmed cell death 4 (Pdcd4) is a novel repressor of in vitro transformation. Pdcd4 directly inhibits the helicase activity of eukaryotic translation initiation factor 4A, a component of the translation initiation complex. To ascertain whether Pdcd4 suppresses tumor development in vivo, we have generated transgenic mice that overexpress Pdcd4 in the epidermis (K14-Pdcd4). K14-regulated Pdcd4 expression caused a neonatal short-hair phenotype due to early catagen entry compared with matched wild-type siblings. In response to the 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) mouse skin carcinogenesis protocol, K14-Pdcd4 mice showed significant reductions in papilloma formation, carcinoma incidence, and papilloma-to-carcinoma conversion frequency compared with wild-type mice. The translational efficiency of an mRNA engineered to form a structured 5' untranslated region (UTR) was attenuated in primary keratinocytes when Pdcd4 was overexpressed. Pdcd4 inhibited by 46% TPA-induced activator protein-1 (AP-1)-dependent transcription, an event required for tumorigenesis. CDK4 and ornithine decarboxylase (ODC) are candidates for Pdcd4-regulated translation as their mRNAs contain 5'structured UTRs. In K14-Pdcd4 primary keratinocytes expressing activated Ha-Ras to mimic DMBA-initiated epidermis, ODC and CDK4 protein levels were decreased by 40% and 46%, respectively. Expression of a protein encoded by 5' unstructured mRNA showed no change. These results extend to an in vivo model the observations that Pdcd4 inhibits both translation initiation and AP-1 activation while decreasing benign tumor development and malignant progression. The K14-Pdcd4 mice seem to validate translation initiation as a novel target for cancer prevention. |
