Normal function of the Rb/E2F tumor suppressor pathway is compromised in all human tumors. Therefore, its function and regulation are areas of critical importance and intense interest for cancer research. pRb controls the cell cycle transition from G1- to S-phase through its repression of the E2F transcription factors. The Rb/E2F pathway regulates a diverse set of activities, and an investigation into the functional components that comprise the pathway would provide valuable insight into the biology of cancer. To obtain a deeper understanding of the Rb/E2F pathway, I propose to decompose the pathway into its constituent functional components using a computational approach, and then to investigate the associations among the functions, regulatory mechanisms, and clinical significance of the pathway components. In addition, I will also elucidate the functional relationships between the intertwined Rb/E2F and p53 pathways, yielding novel insight into the complex interactions between these tumor suppressor pathways. To investigate these issues, I will leverage methods I previously developed to decompose pathways and to infer the transcriptional regulatory proteins that drive their expression. Thus, the goals of this proposal are: (1) to decompose the Rb/E2F pathway into a series of independently functional pathway components regulated by identifiable transcriptional regulatory proteins, (2) to evaluate the correspondence between the components of the Rb/E2F pathway and identified regulators of the cell cycle, and (3) to identify components that connect the intertwined Rb/E2F (cell cycle initiation) and p53 (apoptosis) pathways. These studies would lead to the development of novel methodologies that provide the opportunity to obtain a deeper understanding of the precise components that effect pathway functions, and elucidate the functional connections among the interrelated pathways in a general cellular context, a goal of systems biology. Ultimately, the ability to characterize and measure individual facets of pathway activity will facilitate the development of ever more finely tuned personalized therapeutics.

Public Health Relevance

TO PUBLIC HEALTH Rb is a tumor suppressor that is dysfunctional in all cancers, leading to a cascade of various poorly understood activities brought about by the E2F proteins. I propose to develop computational methods to identify these activities and study them individually, instead of as a whole. I believe that this will lead to a deeper understanding of the function of this pathway, as well as the drugs that target it.

Agency
National Institute of Health (NIH)
Institute
National Library of Medicine (NLM)
Type
Research Transition Award (R00)
Project #
5R00LM009837-05
Application #
8331380
Study Section
Biomedical Library and Informatics Review Committee (BLR)
Program Officer
Ye, Jane
Project Start
2010-09-30
Project End
2014-09-29
Budget Start
2012-09-30
Budget End
2014-09-29
Support Year
5
Fiscal Year
2012
Total Cost
$229,754
Indirect Cost
$76,585
Name
University of Texas Health Science Center Houston
Department
Biology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Soundararajan, Rama; Paranjape, Anurag N; Barsan, Valentin et al. (2015) A novel embryonic plasticity gene signature that predicts metastatic competence and clinical outcome. Sci Rep 5:11766
Gong, X; Yi, J; Carmon, K S et al. (2015) Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness. Oncogene 34:4692-701
Bild, Andrea H; Chang, Jeffrey T; Johnson, W Evan et al. (2014) A field guide to genomics research. PLoS Biol 12:e1001744
Taube, Joseph H; Malouf, Gabriel G; Lu, Emily et al. (2013) Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties. Sci Rep 3:2687
Hollier, Brett G; Tinnirello, Agata A; Werden, Steven J et al. (2013) FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer. Cancer Res 73:1981-92
Chang, Jeffrey T; Mani, Sendurai A (2013) Sheep, wolf, or werewolf: cancer stem cells and the epithelial-to-mesenchymal transition. Cancer Lett 341:16-23
Lin, Shu-Hong; Beane, Lauren; Chasse, Dawn et al. (2013) Cross-platform prediction of gene expression signatures. PLoS One 8:e79228
Chang, Jeffrey T (2012) Deriving transcriptional programs and functional processes from gene expression databases. Bioinformatics 28:1122-9
Cheng, Qing; Chang, Jeffrey T; Geradts, Joseph et al. (2012) Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer. Breast Cancer Res 14:R62
Chang, Jeffrey T; Gatza, Michael L; Lucas, Joseph E et al. (2011) SIGNATURE: a workbench for gene expression signature analysis. BMC Bioinformatics 12:443

Showing the most recent 10 out of 19 publications