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Cited by 212Cancer-related Molecular PathwaysRNA and protein synthesis mechanismsMechanisms of cancer metastasis

Epidermal Expression of the Translation Inhibitor Programmed Cell Death 4 Suppresses Tumorigenesis

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Jansen, Aaron P., Camalier, Corinne E., Colburn, Nancy H.·2005·Cancer Research
DOI 10.1158/0008-5472.can-04-2119
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Abstract

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.

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  • Transgenic mice overexpressing Pdcd4 in the epidermis under the K14 promoter show significant reduction in papilloma formation, carcinoma incidence, and papilloma to carcinoma conversion frequency in response to TPA compared with wild-type mice.

    “The skin of K14-regulated mice shows significant reduction in papilloma formation, carcinoma incidence, and papilloma to carcinoma conversion frequency in response to the tumor promotor TPA, compared with wild-type mice.”

    From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [22]

  • Pdcd4 functions as an inhibitor of neoplastic transformation.

    “These results indicate that Pdcd4 functions as the inhibitor of neoplastic transformation [22].”

    From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [22]

  • The anti-tumor activity of PDCD4 is documented in Pdcd4 transgenic and knockdown mice.

    “and in Pdcd4 transgenic and knockdown mice [21,22].”

    From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [22]

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References 49 · Cited by 212

Research works printed but not linked: 44

  1. Hershey JWB, Miyamoto S. Translational control and cancer. In: Sonenberg N, Hershey JWB, Matthews MB, editors. Translational control of gene expression. New York: Cold Spring Harbor Laboratory Press; 2000. p. 637-54.
  2. Holland EC, Sonenberg N, Pandolfi PP, Thomas G. Signaling control of mRNA translation in cancer pathogenesis. Oncogene 2004;23:3138-44.
  3. Lazaris-Karatzas A, Montine KS, Sonenberg N. Malig- nant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5V cap. Nature 1990;345: 544-7.
  4. Lazaris-Karatzas A, Smith MR, Frederickson RM, et al. Ras mediates translation initiation factor 4E-induced malignant transformation. Genes Dev 1992;6:1631-42.
  5. Ruggero D, Montanaro L, Ma L, et al. The translation factor eIF-4E promotes tumor formation and coopera- tes with c-Myc in lymphomagenesis. Nat Med 2004;10: 484-6.
  6. Herbert TP, Kilhams GR, Batty IH, Proud CG. Distinct signalling pathways mediate insulin and phorbol ester- stimulated eukaryotic initiation factor 4F assembly and protein synthesis in HEK 293 cells. J Biol Chem 2000; 275:11249-56.
  7. Eberle J, Krasagakis K, Orfanos CE. Translation initiation factor eIF-4A1 mRNA is consistently overex- pressed in human melanoma cells in vitro . Int J Cancer 1997;71:396-401.
  8. Eberle J, Fecker LF, Bittner JU, Orfanos CE, Geilen CC. Decreased proliferation of human melanoma cell lines caused by antisense RNA against translation factor eIF- 4A1. Br J Cancer 2002;86:1957-62.
  9. De Benedetti A, Harris AL. eIF4E expression in tumors: its possible role in progression of malignancies. Int J Biochem Cell Biol 1999;31:59-72.
  10. Bauer C, Diesinger I, Brass N, Steinhart H, Iro H, Meese EU. Translation initiation factor eIF-4G is immunogenic, overexpressed, and amplified in patients with squamous cell lung carcinoma. Cancer 2001;92: 822-9.
  11. Rajasekhar VK, Viale A, Socci ND, Wiedmann M, Hu X, Holland EC. Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol Cell 2003;12:889-901.
  12. Ray BK, Lawson TG, Kramer JC, et al. ATP-dependent unwinding of messenger RNA structure by eukaryotic initiation factors. J Biol Chem 1985;260:7651-8.
  13. Cmarik JL, Min H, Hegamyer G, et al. Differentially expressed protein Pdcd4 inhibits tumor promoter- induced neoplastic transformation. Proc Natl Acad Sci U S A 1999;96:14037-42.
  14. Yang HS, Knies JL, Stark C, Colburn NH. Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation. Oncogene 2003;22:3712-20.
  15. Colburn NH, Former BF, Nelson KA, Yuspa SH. Tumour promoter induces anchorage independence irreversibly. Nature 1979;281:589-91.
  16. Colburn NH, Gindhart TD. Specific binding of transforming growth factor correlates with promotion of anchorage independence in EGF receptorless mouse JB6 cells. Biochem Biophys Res Commun 1981; 102:799-807.
  17. Dong Z, Ma W, Huang C, Yang CS. Inhibition of tumor promoter-induced activator protein 1 activation and cell transformation by tea polyphenols, (À)- epigallocatechin gallate, and theaflavins. Cancer Res 1997;57:4414-9.
  18. Li JJ, Rhim JS, Schlegel R, Vousden KH, Colburn NH. Expression of dominant negative Jun inhibits elevated AP-1 and NF-nB transactivation and sup- presses anchorage independent growth of HPV immortalized human keratinocytes. Oncogene 1998; 16:2711-21.
  19. Young MR, Li JJ, Rincon M, et al. Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. Proc Natl Acad Sci U S A 1999;96:9827-32.
  20. Boutwell RK. The function and mechanism of promoters of carcinogenesis. CRC Crit Rev Toxicol 1974;2:419-43.
  21. Verma AK, Conrad EA, Boutwell RK. Induction of mouse epidermal ornithine decarboxylase activity and skin tumors by 7,12-dimethylben. Carcinogenesis 1980; 1:607-11.
  22. Furstenberger G, Kinzel V, Schwarz M, Marks F. Partial inversion of the initiation-promotion sequence of multistage tumorigenesis in the skin of NMRI mice. Science 1985;230:76-8.
  23. Slaga TJ, Budunova IV, Gimenez-Conti IB, Aldaz CM. The mouse skin carcinogenesis model. J Investig Dermatol Symp Proc 1996;1:151-6.
  24. Yuspa SH. Overview of carcinogenesis: past, present and future. Carcinogenesis 2000;21:341-4.
  25. Vassar R, Fuchs E. Transgenic mice provide new insights into the role of TGF-a during epidermal development and differentiation. Genes Dev 1991;5: 714-27.
  26. Dlugosz AA, Glick AB, Tennenbaum T, Weinberg WC, Yuspa SH. Isolation and utilization of epidermal keratinocytes for oncogene research. Methods Enzymol 1995;254:3-20.
  27. Morgenstern JP, Land H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper- free packaging cell line. Nucleic Acids Res 1990;18: 3587-96.
  28. Rincon M, Flavell RA. AP-1 transcriptional activity requires both T-cell receptor-mediated and co-stimula- tory signals in primary T lymphocytes. EMBO J 1994; 13:4370-81.
  29. Svitkin YV, Pause A, Haghighat A, et al. The requirement for eukaryotic initiation factor 4A (elF4A) in translation is in direct proportion to the degree of mRNA 5V secondary structure. RNA 2001;7: 382-94.
  30. Yang HS, Cho MH, Zakowicz H, Hegamyer G, Sonenberg N, Colburn NH. A novel function of the MA-3 domains in transformation and translation suppressor Pdcd4 is essential for its binding to eukaryotic translation initiation factor 4A. Mol Cell Biol 2004;24:3894-906.
  31. Clemens MJ, Bommer UA. Translational control: the cancer connection. Int J Biochem Cell Biol 1999; 31:1-23.
  32. Millet I, Phillips RJ, Sherwin RS, et al. Inhibition of NF-nB activity and enhancement of apoptosis by the neuropeptide calcitonin gene-related peptide. J Biol Chem 2000;275:15114-21.
  33. Goke R, Barth P, Schmidt A, Samans B, Lankat- Buttgereit B. Programmed cell death protein 4 sup- presses CDK1/cdc2 via induction of p21(Waf1/Cip1). Am J Physiol Cell Physiol 2004;287:C1541-6.
  34. Rodriguez-Puebla ML, Miliani de Marval PL, LaCava M, Moons DS, Kiyokawa H, Conti CJ. Cdk4 deficiency inhibits skin tumor development but does not affect normal keratinocyte proliferation. Am J Pathol 2002; 161:405-11.
  35. Thompson EJ, MacGowan J, Young MR, Colburn N, Bowden GT. A dominant negative c-jun specifically blocks okadaic acid-induced skin tumor promotion. Cancer Res 2002;62:3044-7.
  36. Cooper S, Young MR, Colburn N, Bowden GT. Expression of dominant negative c-jun inhibits UVB- induced squamous cell carcinoma number and size in an SKH-1 hairless mouse model. Mole Cancer Res. In press 2005.
  37. Young MR, Farrell L, Lambert PF, Awasthi P, Colburn NH. Protection against human papillomavirus type 16-E7 oncogene-induced tumorigenesis by in vivo expression of dominant-negative c-jun. Mol Carcinog 2002;34:72-7.
  38. Chen Y, Knosel T, Kristiansen G, et al. Loss of PDCD4 expression in human lung cancer correlates with tumour progression and prognosis. J Pathol 2003;200: 640-6.
  39. Muller-Rover S, Handjiski B, van der Veen C, et al. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J Invest Dermatol 2001;117:3-15.
  40. Pena JC, Kelekar A, Fuchs EV, Thompson CB. Manipulation of outer root sheath cell survival perturbs the hair-growth cycle. EMBO J 1999;18:3596-603.
  41. Shibahara K, Asano M, Ishida Y, Aoki T, Koike T, Honjo T. Isolation of a novel mouse gene MA-3 that is induced upon programmed cell death. Gene 1995;166: 297-301.
  42. Kang MJ, Ahn HS, Lee JY, Matsuhashi S, Park WY. Up-regulation of PDCD4 in senescent human diploid fibroblasts. Biochem Biophys Res Commun 2002;293: 617-21.
  43. Onishi Y, Hashimoto S, Kizaki H. Cloning of the TIS gene suppressed by topoisomerase inhibitors. Gene 1998;215:453-9.
  44. Klatt P, Serrano M. Engineering cancer resistance in mice. Carcinogenesis 2003;24:817-26.

Authors
Jansen, A. P., Camalier, C. E., & Colburn, N. H.
Affiliations
Frederick National Laboratory for Cancer Research (US)
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2005-07-15
Volume
65
Issue
14
Pages
6034-6041
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-04-2119
OpenAlex
W2131687108
Cited by
212
References
49
Citations by year
2024: 1 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 9 · 2019: 6 · 2018: 9 · 2017: 7 · 2016: 18 · 2015: 9 · 2014: 15 · 2013: 18 · 2012: 13
FWCI
5.24
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords
PDCD4, translation initiation inhibition, skin carcinogenesis, 5' untranslated region, AP-1 transcription, keratinocytes, ornithine decarboxylase, CDK4, Ha-ras, tumor suppression, cancer prevention
MeSH terms
Animals, Carcinoma, Squamous Cell, Cytoplasm, Epidermis, Female, Luciferases, Mice, Transgenic, Papilloma, Promoter Regions, Genetic, RNA, Messenger, Skin Neoplasms, Protein Biosynthesis, Transcriptional Activation, RNA-Binding Proteins, Disease Progression, Transcription Factor AP-1, 5' Untranslated Regions, Apoptosis Regulatory Proteins, Mice

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