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

被引:200
作者
Jansen, AP [1 ]
Camalier, CE [1 ]
Colburn, NH [1 ]
机构
[1] Natl Canc Inst Frederick, Canc Res Ctr, Lab Canc Prevent, Gene Regulat Sect, Ft Detrick, MD 21702 USA
关键词
D O I
10.1158/0008-5472.CAN-04-2119
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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-Lype 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.
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收藏
页码:6034 / 6041
页数:8
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  • [1] Induction of PDCD4 tumor suppressor gene expression by RAR agonists, antiestrogen and HER-2/neu antagonist in breast cancer cells. Evidence for a role in apoptosis
    Afonja, O
    Juste, D
    Das, S
    Matsuhashi, S
    Samuels, HH
    [J]. ONCOGENE, 2004, 23 (49) : 8135 - 8145
  • [2] Bauer C, 2001, CANCER, V92, P822, DOI 10.1002/1097-0142(20010815)92:4<822::AID-CNCR1388>3.0.CO
  • [3] 2-A
  • [4] Boutwell R K, 1974, CRC Crit Rev Toxicol, V2, P419
  • [5] Loss of PDCD4 expression in human lung cancer correlates with tumour progression and prognosis
    Chen, Y
    Knösel, T
    Kristiansen, G
    Pietas, A
    Garber, ME
    Matsuhashi, S
    Ozaki, I
    Petersen, I
    [J]. JOURNAL OF PATHOLOGY, 2003, 200 (05) : 640 - 646
  • [6] Translational control: the cancer connection
    Clemens, MJ
    Bommer, UA
    [J]. INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 1999, 31 (01) : 1 - 23
  • [7] Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation
    Cmarik, JL
    Min, HZ
    Hegamyer, G
    Zhan, SN
    Kulesz-Martin, M
    Yoshinaga, H
    Matsuhashi, S
    Colburn, NH
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (24) : 14037 - 14042
  • [8] TUMOR PROMOTER INDUCES ANCHORAGE INDEPENDENCE IRREVERSIBLY
    COLBURN, NH
    FORMER, BF
    NELSON, KA
    YUSPA, SH
    [J]. NATURE, 1979, 281 (5732) : 589 - 591
  • [9] SPECIFIC BINDING OF TRANSFORMING GROWTH-FACTOR CORRELATES WITH PROMOTION OF ANCHORAGE INDEPENDENCE IN EGF RECEPTORLESS MOUSE JB6 CELLS
    COLBURN, NH
    GINDHART, TD
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1981, 102 (02) : 799 - 807
  • [10] COOPER S, 2005, IN PRESS MOL CANC RE