Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 14; pp. 6034 - 6041
• Main Authors: JANSEN, Aaron P, CAMALIER, Corinne E, COLBURN, Nancy H
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.07.2005
• Subjects: 5' Untranslated Regions; Animals; Antineoplastic agents; Apoptosis Regulatory Proteins; Biological and medical sciences; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - prevention & control; Cytoplasm - metabolism; Disease Progression; Epidermis - metabolism; Epidermis - pathology; Female; Luciferases - antagonists & inhibitors; Luciferases - biosynthesis; Luciferases - genetics; Medical sciences; Mice; Mice, Transgenic; Papilloma - genetics; Papilloma - metabolism; Papilloma - pathology; Papilloma - prevention & control; Pharmacology. Drug treatments; Promoter Regions, Genetic; Protein Biosynthesis; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA-Binding Proteins - biosynthesis; RNA-Binding Proteins - genetics; RNA-Binding Proteins - physiology; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Skin Neoplasms - prevention & control; Transcription Factor AP-1 - antagonists & inhibitors; Transcription Factor AP-1 - physiology; Transcriptional Activation; Tumors; Translation; Cell death; Epidermis; Inhibitor; Gene expression; Carcinogenesis; Genetic translation; Apoptosis
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-2119

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.