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Gene Review

Pdcd4  -  programmed cell death 4

Mus musculus

Synonyms: D19Ucla1, MA-3, Ma3, Programmed cell death protein 4, Protein MA-3, ...
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Disease relevance of Pdcd4

  • 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 [1].
  • The transformation suppressor gene Pdcd4 (programmed cell death gene 4) inhibits the tumor-promoter mediated transformation of mouse keratinocytes and has recently been implicated as a potential tumor suppressor gene in the development of human lung cancer [2].
  • We recently cloned the cDNA TIS (topoisomerase inhibitor-suppressed) in RVC lymphoma cells exposed to the topoisomerase inhibitors [3].
  • Considering that topoisomerase I is an essential enzyme in mammalian cells, the TIS protein may have an important role in camptothecin toxicity [3].
  • Among such clones, the MA-3 mRNA was induced in all apoptosis-inducible cell lines tested so far, including thymocytes, T cells, B cells and pheochromocytoma [4].

High impact information on Pdcd4


Chemical compound and disease context of Pdcd4


Biological context of Pdcd4


Anatomical context of Pdcd4

  • In vivo translation assays showed that Pdcd4 inhibited cap-dependent but not internal ribosome entry site (IRES)-dependent translation [6].
  • A Northern blot analysis showed that the TIS was expressed in most mouse tissues; at the highest level in the liver and to less extent in the heart and skeletal muscle [3].
  • The MA-3 mRNA was strongly expressed in the thymus although small amounts of the MA-3 mRNA were ubiquitously expressed in mouse adult tissues [4].
  • TIS genes are rapidly and transiently induced by tetradecanoyl phorbol acetate in 3T3 cells [10].
  • Our analysis here of the expression of these genes in the testis of the cAMP-responsive element modulator (CREM)-null mouse revealed that 54 TISP genes are under the transcriptional regulation of CREM [11].

Associations of Pdcd4 with chemical compounds


Co-localisations of Pdcd4


Regulatory relationships of Pdcd4


Other interactions of Pdcd4

  • In a Gal4 fusion assay, Pdcd4 specifically inhibited activation of c-Jun and c-Fos activation domains, but did not inhibit activation of JunB, JunD, Fra-1, or Fra-2 [8].
  • The Pdcd4 protein has weak homology to the eucaryotic translation initiation factor eIF4G and has been shown to interact with certain translation initiation factors [9].
  • These results indicate that Pdcd4 functions as a transformation suppressor, possibly through inhibiting AP-1 activation in combination with other factors such as enhancing NF-kappaB activation [14].
  • Independent of these studies, the Pdcd4 gene has been implicated in the suppression of tumor-promoter-mediated transformation of keratinocytes and as a downstream target of Myb in hematopoietic cells [9].

Analytical, diagnostic and therapeutic context of Pdcd4


  1. Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis. Jansen, A.P., Camalier, C.E., Colburn, N.H. Cancer Res. (2005) [Pubmed]
  2. Transformation suppressor protein Pdcd4 interferes with JNK-mediated phosphorylation of c-Jun and recruitment of the coactivator p300 by c-Jun. Bitomsky, N., Böhm, M., Klempnauer, K.H. Oncogene (2004) [Pubmed]
  3. Cloning of the TIS gene suppressed by topoisomerase inhibitors. Onishi, Y., Hashimoto, S., Kizaki, H. Gene (1998) [Pubmed]
  4. Isolation of a novel mouse gene MA-3 that is induced upon programmed cell death. Shibahara, K., Asano, M., Ishida, Y., Aoki, T., Koike, T., Honjo, T. Gene (1995) [Pubmed]
  5. Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation. Cmarik, J.L., Min, H., Hegamyer, G., Zhan, S., Kulesz-Martin, M., Yoshinaga, H., Matsuhashi, S., Colburn, N.H. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  6. The transformation suppressor Pdcd4 is a novel eukaryotic translation initiation factor 4A binding protein that inhibits translation. Yang, H.S., Jansen, A.P., Komar, A.A., Zheng, X., Merrick, W.C., Costes, S., Lockett, S.J., Sonenberg, N., Colburn, N.H. Mol. Cell. Biol. (2003) [Pubmed]
  7. Differential expression of TIS21 and TIS1 genes in the various organs of Balb/c mice, thymic carcinoma tissues and human cancer cell lines. Lim, I.K., Lee, M.S., Lee, S.H., Kim, N.K., Jou, I., Seo, J.S., Park, S.C. J. Cancer Res. Clin. Oncol. (1995) [Pubmed]
  8. Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation. Yang, H.S., Knies, J.L., Stark, C., Colburn, N.H. Oncogene (2003) [Pubmed]
  9. The transformation suppressor protein Pdcd4 shuttles between nucleus and cytoplasm and binds RNA. Böhm, M., Sawicka, K., Siebrasse, J.P., Brehmer-Fastnacht, A., Peters, R., Klempnauer, K.H. Oncogene (2003) [Pubmed]
  10. Tumor promoter-inducible genes are differentially expressed in the developing mouse. Tippetts, M.T., Varnum, B.C., Lim, R.W., Herschman, H.R. Mol. Cell. Biol. (1988) [Pubmed]
  11. Transcription factors, cAMP-responsive element modulator (CREM) and Tisp40, act in concert in postmeiotic transcriptional regulation. Nagamori, I., Yomogida, K., Adams, P.D., Sassone-Corsi, P., Nojima, H. J. Biol. Chem. (2006) [Pubmed]
  12. Protein aggregation as primary and characteristic cell reaction to various stresses. Kabakov, A.E., Gabai, V.L. Experientia (1993) [Pubmed]
  13. Aerosol delivery of urocanic acid-modified chitosan/programmed cell death 4 complex regulated apoptosis, cell cycle, and angiogenesis in lungs of K-ras null mice. Jin, H., Kim, T.H., Hwang, S.K., Chang, S.H., Kim, H.W., Anderson, H.K., Lee, H.W., Lee, K.H., Colburn, N.H., Yang, H.S., Cho, M.H., Cho, C.S. Mol. Cancer Ther. (2006) [Pubmed]
  14. A novel transformation suppressor, Pdcd4, inhibits AP-1 transactivation but not NF-kappaB or ODC transactivation. Yang, H.S., Jansen, A.P., Nair, R., Shibahara, K., Verma, A.K., Cmarik, J.L., Colburn, N.H. Oncogene (2001) [Pubmed]
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