Biopolym. Cell. 2012; 28(5):404-410.
http://dx.doi.org/10.7124/bc.00006C
Bioinformatics
PTI-1: novel way to oncogenicity
1Vislovukh A. A., 1Shalak V. F., 1Savytskyi O. V., 1Kovalenko N. I., 1, 2Gralievska N. L., 1Negrutskii B. S., 1El'skaya A. V.
  1. State Key Laboratory of Molecular and Cellular Biology
    Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680
  2. Educational and Scientific Center "Institute of Biology",
    Taras Shevchenko National University of Kyiv
    64/13, Volodymyrska Str., Kyiv, Ukraine, 01601

Abstract

Aim. The prostate tumor-inducing oncogene (PTI-1), presumably encoding a truncated form of eukaryotic translation elongation factor 1A1 (eEF1A1), was discovered as a gene overexpressed in prostate tumor samples and absent in normal tissues. The mechanism of PTI-1 oncogenicity remains obscure. Methods. Several bioinformatics methods were applied to analyze the PTI-1 mRNA structure, translation efficiency and coding potential. Results. In silico analysis of 5'UTR of its mRNA suggest that PTI-1 mRNA most probably belongs to the class of templates with low translation efficiency. Additionally, novel open reading frame (ORF) starting with alternative initiation site situated upstream of the main ORF start codon was found. Finally, the peptide that does not resemble eEF1A1 but is partially homologous to relaxin can be synthesized. Conclusions. We suggest that the alternative upstream start codon may initiate synthesis of a peptide (uPTI-1) homologous to relaxin, the hormone shown to promote the prostate cancer progression. uPTI-1 protein may interact with the respective relaxin-specific receptors, suggesting that the tumorigenic outcome of PTI-1 is possibly realized via the relaxin-dependent pathway.
Keywords: prostate cancer, PTI-1, eEF1A1, non-coding RNA, relaxin, ORF, uAUG
Full text: (PDF, in English)

Supplementary data

References

[1] Sun Y., Lin J., Katz A. E., Fisher P. B. Human prostatic carcinoma oncogene PTI-1 is expressed in human tumor cell lines and prostate carcinoma patient blood samples Cancer Res 1997 57, N 1:18–23.
[2] Bertram J., Palfner K., Hiddemann W., Kneba M. Overexpression of ribosomal proteins L4 and L5 and the putative alternative elongation factor PTI-1 in the doxorubicin resistant human colon cancer cell line LoVoDxR Eur. J. Cancer 1998 34, N 5:731–736.
[3] Beyer-Sehlmeyer G., Hiddemann W., Wormann B., Bertram J. Suppressive subtractive hybridisation reveals differential expression of serglycin, sorcin, bone marrow proteoglycan and prostatetumour-inducing gene I (PTI-1) in drug-resistant and sensitive tumour cell lines of haematopoetic origin Eur. J. Cancer 1999 35, N 12:1735–1742.
[4] Ohnami S., Matsumoto N., Nakano M., Aoki K., Nagasaki K., Sugimura T., Terada M., Yoshida T. Identification of genes showing differential expression in antisense K-ras-transduced pancreatic cancer cells with suppressed tumorigenicity Cancer Res 1999 59, N 21:5565–5571.
[5] Shen R., Su Z. Z., Olsson C. A., Fisher P. B. Identification of the human prostatic carcinoma oncogene PTI-1 by rapid expression cloning and differential RNA display Proc. Natl Acad. Sci. USA 1995 92, N 15:6778–6782.
[6] Mansilla F., Hansen L. L., Jakobsen H., Kjeldgaard N. O., Clark B. F., Knudsen C. R. Deconstructing PTI-1: PTI-1 is a truncated, but not mutated, form of translation elongatin factor 1A1, eEF1A1 Biochim. Biophys. Acta 2005 1727, N 2:116–124.
[7] Scaggiante B., Bonin S., Cristiano L., Siracusano S., Stanta G., Dapas B., Giansante C., Fiotti N., Grassi G. Prostate-tumor-inducing gene-1 analysis in human prostate cancer cells and tissue in relation to Mycoplasma infection Cancer Invest 2008 26, N 8:800–808.
[8] Ketcham C. M., Anai S., Reutzel R., Sheng S., Schuster S. M., Brenes R. B., Agbandje-McKenna M., McKenna R., Rosser C. J., Boehlein S. K. p37 induces tumor invasiveness Mol. Cancer Ther 2005 4, N 7:1031–1038.
[9] Binder C., Hagemann T., Husen B., Schulz M., Einspanier A. Relaxin enhances in vitro invasiveness of breast cancer cell lines by up-regulation of matrix metalloproteases Mol. Hum. Reprod 2002 8, N 9:789–796.
[10] Eswar N., Eramian D., Webb B., Shen M. Y., Sali A. Protein structure modeling with MODELLER Methods Mol. Biol 2008 426:145–159.
[11] Davis J. H., Bradley E. K., Miljanich G. P., Nadasdi L., Ramachandran J., Basus V. J. Solution structure of omega-conotoxin GVIA using 2-D NMR spectroscopy and relaxation matrix analysis Biochemistry 1993 32, N 29:7396–7405.
[12] Eigenbrot C., Randal M., Quan C., Burnier J., O'Connell L., Rinderknecht E., Kossiakoff A. A. X-ray structure of human relaxin at 1.5 C. Comparison to insulin and implications for receptor binding determinants J. Mol. Biol 1991 221, N 1:15–21.
[13] TranQui D., Jesior J. C. Structure of the ferredoxin from Clostridium acidurici: model at 1.8 C resolution Acta Crystallogr. D Biol. Crystallogr 1995 51, Pt 2:155–159.
[14] Shen M. Y., Sali A. Statistical potential for assessment and prediction of protein structures Protein Sci 2006 15, N 11:2507–2524.
[15] Chen V. B., Arendall W. B., Headd J. J., Keedy D. A., Immormino R. M., Kapral G. J., Murray L. W., Richardson J. S., Richardson D. C. MolProbity: all-atom structure validation for macromolecular crystallography Acta Crystallogr. D Biol. Crystallogr 66, Pt 1:12–21.
[16] Salnikov A., Sliusar I., Sudakov O., Savytskyi O., Kornelyuk A. Virtual laboratory MOLDYNGRID as a part of scientific infrastructure for biomolecular simulations Int. J. Comput 2010 9, N 4:295–301.
[17] Humphrey W., Dalke A., Schulten K. VMD: visual molecular dynamics J. Mol. Graph 1996 14, N 1:33–38.
[18] Pettersen E. F., Goddard T. D., Huang C. C., Couch G. S., Greenblatt D. M., Meng E. C., Ferrin T. E. UCSF Chimera – a visualization system for exploratory research and analysis J. Comput. Chem 2004 25, N 13:1605–1612.
[19] Meijer H. A., Thomas A. A. Control of eukaryotic protein synthesis by upstream open reading frames in the 5'-untranslated region of an mRNA Biochem. J 2002 367, Pt 1:1–11.
[20] Pickering B. M., Willis A. E. The implications of structured 5' untranslated regions on translation and disease Semin. Cell Dev. Biol 2005 16, N 1:39–47.
[21] Davuluri R. V., Suzuki Y., Sugano S., Zhang M. Q. CART classification of human 5' UTR sequences Genome Res 2000 10, N 11:1807–1816.
[22] Geballe A. P., Morris D. R. Initiation codons within 5'-leaders of mRNAs as regulators of translation Trends Biochem. Sci 1994 19, N 4:159–164.
[23] Morris D. R., Geballe A. P. Upstream open reading frames as regulators of mRNA translation Mol. Cell Biol 2000 20, N 23:8635–8642.
[24] Hofacker I. L., Priwitzer B., Stadler P. F. Prediction of locally stable RNA secondary structures for genome-wide surveys Bioinformatics 2004 20, N 2:186–190.
[25] Kozak M. Circumstances and mechanisms of inhibition of translation by secondary structure in eukaryotic mRNAs Mol. Cell Biol 1989 9, N 11:5134–5142.
[26] Su Z., Goldstein N. I., Fisher P. B. Antisense inhibition of the PTI-1 oncogene reverses cancer phenotypes Proc. Natl Acad. Sci. USA 1998 95, N 4:1764–1769.
[27] Ebert M. S., Sharp P. A. MicroRNA sponges: progress and possibilities RNA 2010 16, N 11:2043–2050.
[28] Luzi E., Marini F., Tognarini I., Carbonell Sala S., Galli G., Falchetti A., Brandi M. L. Ribozyme-mediated compensatory induction of menin-oncosuppressor function in primary fibroblasts from MEN1 patients Cancer Gene Ther 2010 17, N 11:814–825.
[29] Grillo G., Turi A., Licciulli F., Mignone F., Liuni S., Banfi S., Gennarino V. A., Horner D. S., Pavesi G., Picardi E., Pesole G. UTRdb and UTRsite (RELEASE 2010): a collection of sequences and regulatory motifs of the untranslated regions of eukaryotic mRNAs Nucleic Acids Res 38 (Database issue) D75–80.
[30] Bengert P., Dandekar T. A software tool-box for analysis of regulatory RNA elements Nucleic Acids Res 2003 31, N 13:3441–3445.
[31] Jacobs G. H., Chen A., Stevens S. G., Stockwell P. A., Black M. A., Tate W. P., Brown C. M. Transterm: a database to aid the analysis of regulatory sequences in mRNAs Nucleic Acids Res 2009 37 (Database issue) D 72–76.
[32] Stothard P. The sequence manipulation suite: JavaScript programs for analyzing and formatting protein and DNA sequences Biotechniques 2000 28, N 6:1102, 1104.
[33] Martinez A., Traverso J. A., Valot B., Ferro M., Espagne C., Ephritikhine G., Zivy M., Giglione C., Meinnel T. Extent of Nterminal modifications in cytosolic proteins from eukaryotes Proteomics 2008 8, N 14:2809–2831.
[34] Frottin F., Martinez A., Peynot P., Mitra S., Holz R. C., Giglione C., Meinnel T. The proteomics of N-terminal methionine cleavage Mol. Cell Proteomics 2006 5, N 12:2336–2349.
[35] Soding J. Protein homology detection by HMM-HMM comparison Bioinformatics 2005 21, N 7:951–960.
[36] Feng S., Agoulnik I. U., Bogatcheva N. V., Kamat A. A., KwabiAddo B., Li R., Ayala G., Ittmann M. M., Agoulnik A. I. Relaxin promotes prostate cancer progression Clin. Cancer Res 2007 13, N 6:1695–1702.
[37] Feng S., Agoulnik I. U., Truong A., Li Z., Creighton C. J., Kaftanovskaya E. M., Pereira R., Han H. D., Lopez-Berestein G., Klonisch T., Ittmann M. M., Sood A. K., Agoulnik A. I. Suppression of relaxin receptor RXFP1 decreases prostate cancer growth and metastasis Endocr. Relat. Cancer 2010 17, N 4:1021– 1033.
[38] Bullesbach E. E., Schwabe C. LGR8 signal activation by the relaxin-like factor J. Biol. Chem 2005 280, N 15:14586– 14590.
[39] Zhang S., Hughes R. A., Bathgate R. A., Shabanpoor F., Hossain M. A., Lin F., van Lierop B., Robinson A. J., Wade J. D. Role of the intra-A-chain disulfide bond of insulin-like peptide 3 in binding and activation of its receptor, RXFP2 Peptides 2010 31, N 9:1730–1736.
[40] Chou K. C., Shen H. B. A new method for predicting the subcellular localization of eukaryotic proteins with both single and multiple sites: Euk-mPLoc 2.0 PLoS One 2010 5, N 4 e9931.
[41] Blum T., Briesemeister S., Kohlbacher O. MultiLoc2: integrating phylogeny and Gene Ontology terms improves subcellular protein localization prediction BMC Bioinformatics 2009 10:274.
[42] Horton P., Park K. J., Obayashi T., Fujita N., Harada H., AdamsCollier C. J., Nakai K. WoLF PSORT: protein localization predictor Nucleic Acids Res 2007 35 (Web Server issue) W585–587.
[43] Chou K. C., Shen H. B. Cell-PLoc: a package of Web servers for predicting subcellular localization of proteins in various organisms Nat. Protoc 2008 3, N 2:153–162.
[44] Ivell R., Kotula-Balak M., Glynn D., Heng K., Anand-Ivell R. Relaxin family peptides in the male reproductive system – a critical appraisal Mol. Hum. Reprod 2011 17, N 2:71–84.
[45] Hombach-Klonisch S., Bialek J., Trojanowicz B., Weber E., Holzhausen H. J., Silvertown J. D., Summerlee A. J., Dralle H., Hoang-Vu C., Klonisch T. Relaxin enhances the oncogenic potential of human thyroid carcinoma cells Am. J. Pathol 2006 169, N 2:617–632.
[46] Kamat A. A., Feng S., Agoulnik I. U., Kheradmand F., Bogatcheva N. V., Coffey D., Sood A. K., Agoulnik A. I. The role of relaxin in endometrial cancer Cancer Biol. Ther 2006 5, N 1:71–77.
[47] Chan L. J., Hossain M. A., Samuel C. S., Separovic F., Wade J. D. The relaxin peptide family – structure, function and clinical applications Protein Pept. Lett 2011 18, N 3:220–229.