Unraveling dynamic activities of autocrine pathways that control drug-response transcriptome networks

Yoshinori Tamada, Hiromitsu Araki, Seiya Imoto, Masao Nagasaki, Atsushi Doi, Yukiko Nakanishi, Yuki Tomiyasu, Kaori Yasuda, Ben Dunmore, Deborah Sanders, Sally Humphreys, Cristin Print, D. Stephen Charnock-Jones, Kousuke Tashiro, Satoru Kuhara, Satoru Miyano

Research output: Chapter in Book/Report/Conference proceedingConference contribution

11 Citations (Scopus)

Abstract

Some drugs affect secretion of secreted proteins (e.g. cytokines) released from target cells, but it remains unclear whether these proteins act in an autocrine manner and directly effect the cells on which the drugs act. In this study, we propose a computational method for testing a biological hypothesis: there exist autocrine signaling pathways that are dynamically regulated by drug response transcriptome networks and control them simultaneously. If such pathways are identified, they could be useful for revealing drug mode-of-action and identifying novel drug targets. By the node-set separation method proposed, dynamic structural changes can be embedded in transcriptome networks that enable us to find master-regulator genes or critical paths at each observed time. We then combine the protein-protein interaction network with the estimated dynamic transcriptome network to discover drug-affected autocrine pathways if they exist. The statistical significance (p-values) of the pathways are evaluated by the meta-analysis technique. The dynamics of the interactions between the transcriptome networks and the signaling pathways will be shown in this framework. We illustrate our strategy by an application using anti-hyperlipidemia drug, Fenofibrate. From over one million protein-protein interaction pathways, we extracted significant 23 autocrine-like pathways with the Bonferroni correction, including VEGF-NRP1-GIPC1-PRKCA-PPARα, that is one of the most significant ones and contains PPARα, a target of Fenofibrate.

Original languageEnglish
Title of host publicationPacific Symposium on Biocomputing 2009, PSB 2009
Pages251-263
Number of pages13
Publication statusPublished - 2009
Event14th Pacific Symposium on Biocomputing, PSB 2009 - Kohala Coast, HI, United States
Duration: Jan 5 2009Jan 9 2009

Publication series

NamePacific Symposium on Biocomputing 2009, PSB 2009

Other

Other14th Pacific Symposium on Biocomputing, PSB 2009
CountryUnited States
CityKohala Coast, HI
Period1/5/091/9/09

All Science Journal Classification (ASJC) codes

  • Computational Theory and Mathematics
  • Biomedical Engineering
  • Medicine(all)

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