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EIF5A2  -  eukaryotic translation initiation factor 5A2

Homo sapiens

Synonyms: EIF-5A2, Eukaryotic initiation factor 5A isoform 2, Eukaryotic translation initiation factor 5A-2, eIF-5A-2, eIF-5A2, ...
 
 
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Disease relevance of EIF5A2

  • EIF5A2 was discovered as a gene that is expressed in normal tissues, like testis (highly) and brain (at moderate levels) and in tumor-derived cells like colorectal adenocarcinoma. This is in sharp contrast to the ubiquitously expressed EIF5A1 gene [1].
  • Overexperssion in tumor-derived cells correlates with gene copy number [2] [3].
  • Populations of infertile and fertile men were screened for mutations in SPO11 and EIF5A2, two infertility candidate genes, but no correlation with male infertility was found [4].
  • The oncogenic role of eIF5A-2 in the development of ovarian cancer and [5] colorectal cancer candidate was suggested early on [5]. The suggestion has been verified [6] [7] and to also correlate with the disease outcome in urothelial carcinoma [8] [9] and hepatocellular carinoma [10] [11].
  • The corresponding mouse gene, Eif5a2 to be part an amplified region of chromosome 3, nearby Pik3ca [12], like in human ovarian cancers [3]. In the same study Eif5a1 was found to more heavily depend on XPO4 for nucleocytoplasmic export that Eif5a2. The otuhirs also found that nude mice injected with a vector expressiong Eif5a2, but not Eif5a1, triggered tumorogenesis [12]. The authors proposed eIF5A-2 as a target for therapeutic intervention in the 30 % of human breast cancers that have lost XPO4.

High impact information on EIF5A2

  • A candidate oncogene (EIF5A2) encoding eukaryotic initiation factor 5A2 ( eIF5A-2), a member of eukaryotic initiation factor 5A subfamily, was been isolated from a frequently amplified region at 3q26 [5].
  • Furthermore, antisense DNA against EIF5A2 could inhibit cell growth in ovarian cancer cell line UACC-1598 with amplification of EIF5A2 in form of double minutes [5].
  • Cell growth rate in UACC-1598 was also inhibited when the expression level of EIF5A2 was decreased by the reduction of the copy number of double minutes [5].
  • Several candidate oncogenes located on 3q have been proposed, e.g., PIK3CA, p63, and EIF5A2 [13].
  • The proliferation-related function of eIF5A supports that EIF5A2 is a candidate oncogene related to the development of ovarian cancer [14].
 

Biological context of EIF5A2

  • The two human genes EIF5A1 on chromosome 17 (p12-p13) and EIF5A2 on chromosome 3 (q25-q27) respectively, encode eIEF5A-1 (154 amino acids) and eIF5A-2 (153 amino acids) that are and 84 % idential and 94 % similar.
  • EIF5A2 stretches over 17 kb and consists of five exons and four introns [1].
  • Four EIF5A2 mRNAs (0.7, 1.6, 3.8, and 5.6 kb in length) share a 129-nt 5' UTR and a coding sequence for the 153-amino-acid eIF5A-2 protein, but possess four alternative 3' UTRs that arise through differential polyadenylation [1] [2].
  • One EIF5A2-pseudogene is located on chromosome 15.
  • Overexpression of eIF5A-2 mRNA in certain human cancer cells, in contrast to weak normal expression limited to human testis and brain, suggested EIF5A2 as a potential oncogene [15].
  • The eIF5A-2 protein, like the the eIF5A-1 protein, is post-translationally modified with hypusine [16]. Hypusine is essential for its function to stimulate ribosomal peptidyltransfase activity.
  • The eIF5A-proteins are mainly localized to the cytoplasm, and possess an N-terminal nuclear export signal [17]. Export is thought to be mediated by XPO4 [18].
 

Anatomical context of EIF5A2

 

Enzymatic interactions

  • Lysine 50 is the target for hypusine modification. In the first step deoxyhypusine synthase, the encoded by DHPS, adds the aminobutyl part of spermidine to the 6-amine to form deoxyhypusine.
  • N1-guanyl-N1,N7-diaminoheptane, or GC7, is an efficient inhibitor of DHPS [19].
  • In the second step deoxyhypusine hydroxylase (deoxyhypusine mono-oxygenase) DOHH transfers one oxygen to the C-2 of the newly added aminobutly moiety.
  • Iron chelators, such as mimosine, deferoxamine and ciclopirox are efficient inhibitors of DOHH [20] [21].
  • Lysine 47 in eIF5A-1, and by implication also in eIF5A-2, is post-translationally acetylated, by a hitherto unknown acetylase [22].

Other interactions of EIF5A2

  • While the exact binding site on the euokaryotic ribosome has been established, by inference with the bacterial homologue EFP, eIF5A proteins are likely to bind to E-site close to or even inserting the hypusine into the peptidyltransferase center [23].

References

  1. Human eIF5A2 on chromosome 3q25-q27 is a phylogenetically conserved vertebrate variant of eukaryotic translation initiation factor 5A with tissue-specific expression. Jenkins, Z.A., Hååg, P.G., Johansson, H.E. Genomics (2001) [Pubmed]
  2. Differential expression of eIF5A-1 and eIF5A-2 in human cancer cells. Clement, P.M., Johansson, H.E., Wolff, E.C., Park, M.H. FEBS. J. (2006) [Pubmed]
  3. Isolation of a novel candidate oncogene within a frequently amplified region at 3q26 in ovarian cancer. Guan, X.Y., Sham, J.S., Tang, T.C., Fang, Y., Huo, K.K., Yang, J.M. Cancer. Res. (2001) [Pubmed]
  4. Screening the SPO11 and EIF5A2 genes in a population of infertile men. Christensen, G.L., Ivanov, I.P., Atkins, J.F., Mielnik, A., Schlegel, P.N., Carrell, D.T. Fertil. Steril. (2005) [Pubmed]
  5. Oncogenic role of eIF-5A2 in the development of ovarian cancer. Guan, X.Y., Fung, J.M., Ma, N.F., Lau, S.H., Tai, L.S., Xie, D., Zhang, Y., Hu, L., Wu, Q.L., Fang, Y., Sham, J.S. Cancer Res. (2004) [Pubmed]
  6. Overexpression of EIF-5A2 is associated with metastasis of human colorectal carcinoma. Xie, D., Ma, N.F., Pan, Z.Z., Wu, H.X., Liu, Y.D., Wu, G.Q., Kung, H.F., Guan, X.Y. Hum. Pathol. (2008) [Pubmed]
  7. Expression and amplification of eIF-5A2 in human epithelial ovarian tumors and overexpression of EIF-5A2 is a new independent predictor of outcome in patients with ovarian carcinoma. Yang, G.F., Xie, D., Liu, J.H., Luo, J.H., Li, L.J., Hua, W.F., Wu, H.M., Kung, H.F., Zeng, Y.X., Guan, X.Y. Gynecol. Oncol. (2009) [Pubmed]
  8. Overexpression of EIF-5A2 is an independent predictor of outcome in patients of urothelial carcinoma of the bladder treated with radical cystectomy. Chen, W., Luo, J.H., Hua, W.F., Zhou, F.J., Lin, M.C., Kung, H.F., Zeng, Y.X., Guan, X.Y., Xie, D. Cancer. Epidemiol. Biomarkers. Prev. (2009) [Pubmed]
  9. Overexpression of EIF-5A2 predicts tumor recurrence and progression in pTa/pT1 urothelial carcinoma of the bladder. Luo, J.H., Hua, W.F., Rao, H.L., Liao, Y.J., Kung, H.F., Zeng, Y.X., Guan, X.Y., Chen, W., Xie, D. Cancer. Sci. (2009) [Pubmed]
  10. Overexpression of eukaryotic initiation factor 5A2 enhances cell motility and promotes tumor metastasis in hepatocellular carcinoma. Tang, D.J., Dong, S.S., Ma, N.F., Xie, D., Chen, L., Fu, L., Lau, S.H., Li, Y., Li, Y., Guan, X.Y. Hepatology. (2010) [Pubmed]
  11. Prognostic significance and therapeutic potential of eukaryotic translation initiation factor 5A (eIF5A) in hepatocellular carcinoma. Lee, N.P., Tsang, F.H., Shek, F.H., Mao, M., Dai, H., Zhang, C., Dong, S., Guan, X.Y., Poon, R.T., Luk, J.M. Int. J. Cancer. (2010) [Pubmed]
  12. An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer. Zender, L., Xue, W., Zuber, J., Semighini, C.P., Krasnitz, A., Ma, B., Zender, P., Kubicka, S., Luk, J.M., Schirmacher, P., McCombie, W.R., Wigler, M., Hicks, J., Hannon, G.J., Powers, S., Lowe, S.W. Cell. (2008) [Pubmed]
  13. Amplicon mapping and transcriptional analysis pinpoint cyclin L as a candidate oncogene in head and neck cancer. Redon, R., Hussenet, T., Bour, G., Caulee, K., Jost, B., Muller, D., Abecassis, J., du Manoir, S. Cancer Res. (2002) [Pubmed]
  14. Isolation of a novel candidate oncogene within a frequently amplified region at 3q26 in ovarian cancer. Guan, X.Y., Sham, J.S., Tang, T.C., Fang, Y., Huo, K.K., Yang, J.M. Cancer Res. (2001) [Pubmed]
  15. Identification and characterization of eukaryotic initiation factor 5A-2. Clement, P.M., Henderson, C.A., Jenkins, Z.A., Smit-McBride, Z., Wolff, E.C., Hershey, J.W., Park, M.H., Johansson, H.E. Eur. J. Biochem. (2003) [Pubmed]
  16. Identification and characterization of eukaryotic initiation factor 5A-2. Clement, P.M., Henderson, C.A., Jenkins, Z.A., Smit-McBride, Z., Wolff, E.C., Hershey, J.W., Park, M.H., Johansson, H.E. Eur. J. Biochem. (2003) [Pubmed]
  17. The N-terminal region of eukaryotic translation initiation factor 5A signals to nuclear localization of the protein. Parreiras-E-Silva, L.T., Gomes, M.D., Oliveira, E.B., Costa-Neto, C.M. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  18. Exportin 4: a mediator of a novel nuclear export pathway in higher eukaryotes. Lipowsky, G., Bischoff, F.R., Schwarzmaier, P., Kraft, R., Kostka, S., Hartmann, E., Kutay, U., Görlich, D. EMBO. J. (2000) [Pubmed]
  19. Features of the spermidine-binding site of deoxyhypusine synthase as derived from inhibition studies. Effective inhibition by bis- and mono-guanylated diamines and polyamines. Jakus, J., Wolff, E.C., Park, M.H., Folk, J.E. J. Biol. Chem. (1993) [Pubmed]
  20. Evaluation of the metal ion requirement of the human deoxyhypusine hydroxylase from HeLa cells using a novel enzyme assay. Csonga, R., Ettmayer, P., Auer, M., Eckerskorn, C., Eder, J., Klier, H. FEBS. Lett. (1996) [Pubmed]
  21. The antifungal drug ciclopirox inhibits deoxyhypusine and proline hydroxylation, endothelial cell growth and angiogenesis in vitro. Clement, P.M., Hanauske-Abel, H.M., Wolff, E.C., Kleinman, H.K., Park, M.H. Int. J. Cancer. (2002) [Pubmed]
  22. The effect of hypusine modification on the intracellular localization of eIF5A. Lee, S.B., Park, J.H., Kaevel, J., Sramkova, M., Weigert, R., Park, M.H. Biochem. Biophys. Res. Commun. (2009) [Pubmed]
  23. Formation of the first peptide bond: the structure of EF-P bound to the 70S ribosome. Blaha, G., Stanley, R.E., Steitz, T.A. Science. (2009) [Pubmed]
 
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