Abstract
Micro-arrays can identify co-expressed genes at large scale. The gene expression analysis does however not show functional relationships between co-expressed genes. To address this problem, we link gene expression data to protein interaction data. For the gene products of co-expressed genes, we identify structural domains by sequence alignment and threading. Next, we use the protein structure interaction PSIMAP to find structurally interacting domains. Finally, we generate structural and sequence alignments of the original gene products and the identified structures and check conservation of the relevant interaction interfaces. From this analysis, we derive potentially relevant protein interactions for the gene expression data.
We applied this method to co-expressed genes in pancreatic ductal carcinoma. Our method reveals among others a number of functional clusters related to the proteasome, signalling, ubiquitinisation, serine proteases, immunoglobulin and kinases. We investigate the kinase cluster in detail and reveal an interaction between the cell division control protein CDC2 and the cyclin-dependent kinase inhibitor CDKN3, which is also confirmed by literature. Furthermore, our method reveals new interactions between CDKN3 and the cell division protein kinase CDK7 and between CDKN3 and the serine/threonine-protein kinase CDC2L1.
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References
Bader, G.D., Hogue, C.W.: Bind–a data specification for storing and describing biomolecular interactions, molecular complexes and pathways. Bioinformatics 16(5), 465–477 (2000)
Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N., Bourne, P.E.: The protein data bank. Nucleic Acids Res. 28(1), 235–242 (2000)
Gene Ontology Consortium: The gene ontology (go) database and informatics resource. Nucleic Acids Research 32, 258–261 (2004)
Dafas, P., Bolser, D., Gomoluch, J., Park, J., Schroeder, M.: Using convex hulls to extract interaction interfaces from known structures. Bioinformatics 20(10), 1486–1490 (2004)
Deshpande, A., Sicinski, P., Hinds, P.W.: Cyclins and cdks in development and cancer: a perspective. Oncogene 24(17), 2909–2915 (2005)
Grutzmann, R., Saeger, H.D., Luttges, J., Schackertt, H.K., Kalthoff, H., Kloppel, G., Pilarsky, C.: Microarray-based gene expression profiling in pancreatic ductal carcinoma: status quo and perspectives. International Journal of Colorectal Diseases, 401–413 (2004)
Hannon, G.J., Casso, D., Beach, D.: Kap: A dual specificity phosphatase that interacts with cyclin-dependent kinases. Proc of the National Academy of Sciences 91, 1731–1735 (1994)
Ishizawar, R., Parsons, S.J.: c-src and cooperating partners in human cancer. Cancer Cell 6(3), 209–214 (2004)
Jones, D.T.: Genthreader: an efficient and reliable protein fold recognition method for genomic sequences. J. Mol. Biol. 287(4), 797–815 (1999)
Menard, S., Casalini, P., Campiglio, M., Pupa, S.M., Tagliabue, E.: Role of HER2/neu in tumor progression and therapy. Cell Mol. Life Sci. 61(23), 2965–2978 (2004)
Murzin, A.G., Brenner, S.E., Hubbard, T., Chothia, C.: SCOP: A structural classification of proteins database for the investigation of sequences and structures. Journal of Molecular Biology 247(4), 536 (1995)
Park, J., Lappe, M., Teichmann, S.A.: Mapping protein family interactions: intramolecular and intermolecular protein family interaction repertoires in the pdb and yeast. J. Mol. Biol. 307(3), 929–938 (2001)
Pilarsky, C., Wenzig, M., Specht, T., Saeger, H., Grutzmann, R.: Identification and validation of commonly overexpressed genes in solid tumours by comparison of microarray data. Neoplasia (2004)
Poon, R.Y., Hunter, T.: Dephosphorylation of cdk2 thr160 by the cyclin-dependent kinase-interacting phosphatase kap in the absence of cyclin. Science (1995)
Sawyer, T.K.: Novel oncogenic protein kinase inhibitors for cancer therapy. Curr. Med. Chem. Anti-Canc. Agents 4(5), 449–455 (2004)
Tibes, R., Trent, J., Kurzrock, R.: Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu. Rev. Pharmacol Toxicol. 45, 357–384 (2005)
Xenarios, I., Salwinski, L., Duan, X.J., Higney, P., Kim, S.M., Eisenberg, D.: Dip: the database of interacting proteins. Nucleic Acids Research 28(1), 289–291 (2000)
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Dawelbait, G., Pilarsky, C., Zhang, Y., Grützmann, R., Schroeder, M. (2005). Structural Protein Interactions Predict Kinase-Inhibitor Interactions in Upregulated Pancreas Tumour Genes Expression Data. In: R. Berthold, M., Glen, R.C., Diederichs, K., Kohlbacher, O., Fischer, I. (eds) Computational Life Sciences. CompLife 2005. Lecture Notes in Computer Science(), vol 3695. Springer, Berlin, Heidelberg. https://doi.org/10.1007/11560500_1
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DOI: https://doi.org/10.1007/11560500_1
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-29104-6
Online ISBN: 978-3-540-31726-5
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