Comparison of epigenetic changes that have predisposed protein kinase genes to become oncogenes

Liu, Guang Bin and Pioth, Gabriel and Zheng, Qing Yin (2009) Comparison of epigenetic changes that have predisposed protein kinase genes to become oncogenes. In: Case Comprehensive Cancer Center Breast Cancer Retreat 2009, 5-6 Oct 2009, Cleveland, United States.

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BACKGROUND: Protein kinases (PK) are enzymes that regulate cell survival, metabolism, proliferation, communication and apoptosis in mammals via transfer of a terminal phosphate group from adenosine triphosphate to target proteins. A number of genes that encode PKs are overexpressed or amplified in human tumours. This project identified and compared epigenetic changes that have contributed to mammalian PK genes becoming oncogenes.
METHOD: The PK oncogenes (PKO) investigated were obtained from the human kinome using the Online Mendelian Inheritance in Man database. The PKOs obtained were used as a template to download genomic sequences from the Ensembl gene browser into collect1by1 Matlab program. A subordinate Matlab program computed GC content of exon and promoter region CpG densities. The codon usage bias of PKOs was determined using Effective Number of Codon (Nc) and Codon Adaptation Index (CAI) algorithms. Protein kinase oncogenes sequences were also downloaded into Biomanager to construct PK Phylogenetic trees using Neighbour-Joining/UPGMA method version 3.573c.
RESULTS: The study analysis confirmed that human PKOs have more CpGs in the 1000 base pairs upstream region of transcription start sites (TSS) than those found in the mouse, chimpanzee and horse. The human PKOs with high CpG densities in the promoter region were expressed more in tumours than in normal tissues. The GC contents of the protein-coding region were moderately decreased in GC rich oncogenes in primates compared to the horse and mouse. The amino acid residues surrounding the phosphorylation sites of these PKOs differed between species. It is likely that mutations in the PKOs nucleotide sequences have caused this change. CAI and Nc tests confirmed that human PKOs have moved toward high gene expression levels compared to other species. This study also found AKT1, a PKO, is critically involved in tumorigenesis and metastasis. Therefore, targeting this gene’s signalling pathways could impair breast cancer proliferation and angiogenesis.
CONCLUSION: Epigenetic factors may have influenced the increase of CpG density in the human PKO promoter regions as well as causing a slight decrease in the GC content of the protein coding regions. These epigenetic changes coupled with variable mutations at the phosphorylation sites could have elevated the PKOs expression as observed in human cancer tissues. These data suggest that AKT1, a cancer angiogenesis initiator, could be a therapeutic target. Such a therapeutic strategy could improve already prescribed angiogenesis inhibitors used for cancer treatment.

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Item Type: Conference or Workshop Item (Commonwealth Reporting Category E) (Poster)
Refereed: Yes
Item Status: Live Archive
Additional Information: Unable to source copy of publication.
Faculty / Department / School: Historic - Faculty of Sciences - Department of Biological and Physical Sciences
Date Deposited: 14 Dec 2017 02:29
Last Modified: 14 Dec 2017 02:29
Uncontrolled Keywords: Protein kinases; oncogenes; epigenesis
Fields of Research : 06 Biological Sciences > 0601 Biochemistry and Cell Biology > 060102 Bioinformatics
06 Biological Sciences > 0604 Genetics > 060405 Gene Expression (incl. Microarray and other genome-wide approaches)
Socio-Economic Objective: E Expanding Knowledge > 97 Expanding Knowledge > 970106 Expanding Knowledge in the Biological Sciences

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