Meta-analysis of SUMO1

An abundantly growing body of literature implicates conjugation of SUMO in the regulation of many proteins and processes, yet the regulation of SUMO pathways is poorly understood. To gain insight into the players in the SUMO1 pathway I have performed an in-silico co-expression meta-analysis of SUMO1, comparing many different multi-microarray studies of various normal and human tumour tissues, from the Oncomine database. This serves as a data-driven predictor of pathway partners of SUMO1. While the data obtained need to be confirmed by future independent experiments and can currently only be considered a hypothesis, results implicate defender against cell death (DAD1) and the anti-apoptotic DEK oncogene as new pathway partners of SUMO1

Meta-analysis of human cancer microarrays reveals GATA3 is integral to the estrogen receptor alpha pathway

<p>Abstract</p> <p>Background</p> <p>The transcription factor GATA3 has recently been shown to be necessary for mammary gland morphogenesis and luminal cell differentiation. There is also an increasing body of data linking GATA3 to the estrogen receptor α (ERα) pathway. Among these it was shown that GATA3 associates with the promoter of the ERα gene and ERα can reciprocally associate with the GATA3 gene. GATA3 has also been directly implicated in a differentiated phenotype in mouse models of mammary tumourigenesis. The purpose of our study was to compare coexpressed genes, by meta-analysis, of GATA3 and relate these to a similar analysis for ERα to determine the depth of overlap.</p> <p>Results</p> <p>We have used a newly described method of meta-analysis of multiple cancer studies within the Oncomine database, focusing here predominantly upon breast cancer studies. We demonstrate that ERα and GATA3 reciprocally have the highest overlap with one another. Furthermore, we show that when both coexpression meta-analysis lists for ERα and GATA3 are compared there is a significant overlap between both and, like ERα, GATA3 coexpresses with ERα pathway partners such as pS2 (<it>TFF1</it>), <it>TFF3</it>, <it>FOXA1</it>, <it>BCL2</it>, <it>ERBB4</it>, <it>XBP1</it>, <it>NRIP1</it>, <it>IL6ST</it>, keratin 18(<it>KRT18</it>) and cyclin D1 (<it>CCND1</it>). Moreover, as these data are derived from human tumour samples this adds credence to previous cell-culture or murine based studies.</p> <p>Conclusion</p> <p>GATA3 is hypothesized to be integral to the ERα pathway given the following: (1) The large overlap of coexpressed genes as seen by meta-analysis, between GATA3 and ERα, (2) The highest coexpressing gene for GATA3 was ERα and <it>vice-versa</it>, (3) GATA3, like ERα, coexpresses with many well-known ERα pathway partners such as pS2.</p

Identification of novel pathway partners of p68 and p72 RNA helicases through Oncomine meta-analysis

<p>Abstract</p> <p>Background</p> <p>The Oncomine™ database is an online collection of microarrays from various sources, usually cancer-related, and contains many "multi-arrays" (collections of analyzed microarrays, in a single study). As there are often many hundreds of tumour samples/microarrays within a single multi-array results from coexpressed genes can be analyzed, and are fully searchable. This gives a potentially significant list of coexpressed genes, which is important to define pathways in which the gene of interest is involved. However, to increase the likelihood of revealing truly significant coexpressed genes we have analyzed their frequency of occurrence over multiple studies (meta-analysis), greatly increasing the significance of results compared to those of a single study.</p> <p>Results</p> <p>We have used the DEAD-box proteins p68(Ddx5) and p72(Ddx17) as models for this coexpression frequency analysis as there are defined functions for these proteins in splicing and transcription (known functions which we could use as a basis for quality control). Furthermore, as these proteins are highly similar, interact together, and may be to some degree functionally redundant, we then analyzed the overlap between coexpressed genes of p68 and p72. This final analysis gave us a highly significant list of coexpressed genes, clustering mainly in splicing and transcription (recapitulating their published roles), but also revealing new pathways such as cytoskeleton remodelling and protein folding. We have further tested a predicted pathway partner, RNA helicase A(Dhx9) in a reciprocal meta-analysis that identified p68 and p72 as being coexpressed, and further show a direct interaction of Dhx9 with p68 and p72, attesting to the predictive nature of this technique.</p> <p>Conclusion</p> <p>In summary we have extended the capabilities of Oncomine™ by analyzing the frequency of coexpressed genes over multiple studies, and furthermore assessing the overlap with a known pathway partner (in this case p68 with p72). We have shown our predictions corroborate previously published studies on p68 and p72, and that novel predictions can be easily tested. These techniques are widely applicable and should increase the quality of data from future meta-analysis studies.</p

Aggressive International Tax Planning by Multinational Corporations: The Canadian Context and Possible Responses

Aggressive international tax planning by multinational corporations has lately fallen under intense political scrutiny. U.S. politicians have called out some American multinationals, including Apple, Amazon, Starbucks and Google, for relocating profits abroad to avoid American taxes. More recently, politicians accused Burger King of being unpatriotic for its own purported “tax inversion” maneuver, in which it would acquire Canada’s Tim Hortons and shift the head office from Florida to Ontario, benefitting from the lower northern tax rates. The Chicago-based Walgreens pharmacy chain recently backed off a “tax inversion” plan to relocate to Switzerland (the former headquarters of Alliance Boots, a company acquired by Walgreens), apparently having assessed the political risk as too high. This sort of aggressive international tax planning by multinational corporations was what G20 members had committed to fighting against when they endorsed the OECD’s “action plan” against base erosion and profit shifting (BEPS). Canada has been vigilant about improving its tax framework to prevent non-resident corporations from eroding the Canadian tax base, having enacted thin-capitalization rules and, more recently, foreign-affiliate-dumping rules, as well as proposing anti-treaty-shopping measures. But despite Canada’s commitment to the OECD’s BEPS Action Plan, the Canadian government has been reluctant to follow through on implementing rules that might affect its own resident corporations and their international competitiveness. This is most notably visible in the generous participation exemption for dividends from foreign affiliates, the absence of rules restricting the deductibility of interest expenses incurred to earn exempt dividends from foreign affiliates. Canada may be reluctant to fully follow through on all aspects of the OECD’s BEPS Action Plan. As the examples of Apple, Amazon, Google and Starbucks demonstrate, the American government has so far been unable to bring itself to take any meaningful action against aggressive international planning by U.S.resident corporations. Were Canada to enact and enforce rules that clamped down on aggressive international tax planning by its own resident corporations, it would only put Canadian firms at a competitive disadvantage relative to American (or other international) rivals. Until the United States is willing and able to take the lead on aggressive international tax planning by multi-national corporations, the reality is that smaller countries, including Canada, should be cautious about making changes to its international tax rules that are dependent on other countries making similar changes