Transcriptional Regulatory Networks Activated by PI3K and ERK Transduced Growth Signals in Human Glioblastoma Cells

Abstract

Determining how cells regulate their transcriptional response to extracellular signals is key to the understanding of complex eukaryotic systems. This study was initiated with the goals of furthering the study of mammalian transcriptional regulation and analyzing the relative benefits of related computational methodologies. One dataset available for such an analysis involved gene expression profiling of the early growth factor response to platelet derived growth factor (PDGF) in a human glioblastoma cell line; this study differentiated genes whose expression was regulated by signaling through the phosphoinositide-3-kinase (PI3K) versus the extracellular-signal regulated kinase (ERK) pathways. We have compared the inferred transcription factors from this previous study with additional predictions of regulatory transcription factors using two alternative promoter sequence analysis techniques. This comparative analysis, in which the algorithms predict overlapping, although not identical, sets of factors, argues for meticulous benchmarking of promoter sequence analysis methods to determine the positive and negative attributes that contribute to their varying results. Finally, we inferred transcriptional regulatory networks deriving from various signaling pathways using the CARRIE program suite. These networks not only included previously described transcriptional features of the response to growth signals, but also predicted new regulatory features for the propagation and modulation of the growth signal.

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Correspondence to Zhi-Ping Weng.

Additional information

This work was supported by the following grants from the National Institutes of Health: R01 CA81157 to UH, R01 HG03110 to ZW, and P20-GM66401.

Peter M. Haverty received his Bachelor of Science in biological sciences from the University of California at Davis in 1997. Prior to beginning the Ph.D. program in bioinformatics at Boston University, he worked as a laboratory technician at the University of California at Berkeley and completed the certificate program in Bioinformatics at Stanford University. He completed his Ph.D. in bioinformatics at Boston University studying under Zhiping Weng and Ulla Hansen in 2004. His research focused on discovering transcriptional regulatory networks using gene expression and genome sequence data. Dr. Haverty has recently joined the Bioinformatics Department at Genentech, Inc. in South San Francisco, CA.

Zhi-Ping Weng graduated from the University of Science and Technology of China in 1992 with B.S. degree in electrical engineering. In 1993, she entered the graduate program in biomedical engineering at Boston University, and received her Ph.D. degree in 1997. The focus of her thesis research was in computational biology, especially on binding free energy calculations. In January 1997 Dr. Weng was appointed Instructor of Biomedical Engineering at Boston University. In that capacity she taught and conducted research, and had primary responsibility for the development of the Bioinformatics program and the core curriculum in Bioinformatics. In January 1999 the Biomedical Engineering Department at Boston University decided to grow in the area of Bioinformatics. After a national search, the department appointed Dr. Weng a tenure-track assistant professor. In September 2003, Dr. Weng was promoted to Associate Professor with tenure. Dr. Weng's research is focused on developing computational methods to obtain a predictive understanding of protein-protein interaction and transcriptional regulation. Her lab currently has 2 postdocs and 11 graduate students, funded by the National Institutes of Health and the National Science Foundation. She has published over 60 archival journal articles. For more information, please visit Dr. Weng's lab Website (http://zlab.bu.edu).

Ulla Hansen received her A.B. degree in chemistry from Oberlin College in 1974, and her Ph.D. degree in biochemistry and molecular biology from Harvard University in 1979. She was a postdoctoral fellow in the laboratory of Phillip Sharp at MIT for three years, and then joined the faculty of Harvard Medical School as an Assistant Professor at the Dana-Farber Cancer Institute in 1983. She remained at Dana-Farber until 1998, when she moved to her present position as Professor of Biology at Boston University. Throughout her career, Dr. Hansen's research has focused on the regulation of gene expression. As a graduate student in the laboratory of William McClure, she studied the role of the sigma subunit of E. coli RNA polymerase in transcription initiation. She began studies of transcription in mammalian cells as a postdoctoral fellow at MIT, and has continued research in this area. Her contributions have included the first demonstration of active transcriptional repressors (i.e., the Drosophila Kruppel protein) in eukaryotes. Another area of research has focused on her identification and isolation of a cell growth-regulated and cell cycle-regulated transcription factor, LSF, which in turn regulates cell cycle progression. Finally, a major area of her research for many years has regarded how chromatin components contribute to transcriptional regulation at RNA polymerase II promoters. Her laboratory demonstrated that the HMGN class of chromosomal proteins specifically activate transcription by RNA polymerase II on chromatin templates through decompaction of the long-range chromatin structure. She also investigated the role of chromatin in regulation of estrogen-inducible promoters, demonstrating the requirement for histone acetylation to permit the basal transcription machinery to bind and promote transcription initiation.

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Haverty, P.M., Weng, ZP. & Hansen, U. Transcriptional Regulatory Networks Activated by PI3K and ERK Transduced Growth Signals in Human Glioblastoma Cells. J Comput Sci Technol 20, 439–445 (2005). https://doi.org/10.1007/s11390-005-0439-9

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  • PI3K
  • ERK
  • PDGF
  • transcriptional
  • regulatory network
  • cis-element