Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis.
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.
Jansen
Aaron P
AP
Gene Regulation Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA. ajansen@ncifcrf.gov
Camalier
Corinne E
CE
Colburn
Nancy H
NH
D020121:5' Untranslated Regions; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D005260:Female; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D015533:Transcriptional Activation
D020121:5' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; C498443:Pdcd4 protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018808:Transcription Factor AP-1; D008156:Luciferases