Oliver Bogler , Ph.D.
1991, Ludwig Institute for Cancer Research
The University of Texas M. D. Anderson Cancer Center
Department of Neurosurgery & Brain Tumor Center
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Oliver Bogler , Ph.D. 1991, Ludwig Institute for Cancer Research The University of Texas M. D. Anderson Cancer Center |
Research Interests:
There are three main areas of research being pursued in my laboratory:
The role of the adapter molecule SETA/CIN85 in signal transduction in normal and transformed glial cells
SETA is an SH3 domain adapter molecule whose expression is associated with the transformed state in astrocytes [1]. The first interaction we identified for SETA was with another adaptor protein, Alix/AIP1 and its binding partner ALG-2/PCD6, a regulator of apoptosis, and so we began studying the role of SETA in apoptosis [2]. SETA also interacts with the signaling molecules Grb2, the Cbl family and p85 PI3 kinase [3], and the SETA-Alix complex is involved in the regulation of focal adhesion kinases and cell adhesion [4].
SETA has a role in the internalization of receptor tyrosine kinases, including the EGFR and PDGFR, which are important in the progression of gliomas. Together with the Cbl proteins SETA/CIN85 mediates receptor internalization and signal attenuation. We analyzed whether the Cbl-SETA complex also interacted with the ΔEGFR, a mutant associated with glioblastoma, and found that this receptor maintains a low level of activity that allows it to escape downregulation by Cbl-SETA [5]. Interestingly, Alix/AIP1 negatively regulates the Cbl-SETA complex, protecting EGFR from downregulation [6]. We also looked at src, and found that it in turn negatively regulates Alix/AIP1 by phosphorylation [7]. We are pursuing this line of investigation to identify whether these mechanisms can be harnessed to downregulate oncogenic tyrosine kinase signaling in brain tumors.
1. Bögler, O., Furnari, F. B., Kindler-Roehrborn, A., Sykes, V. W., Yung, R., Huang, H.-J. S., and Cavenee, W. K. (2000) SETA: a novel SH3 domain-containing adapter molecule associated with malignancy in astrocytes Neuro-Oncology 2:6-15
2. Chen, B., Borinstein, S. C., Gillis, J., Sykes, V. W., and Bögler, O. (2000) The glioma associated protein SETA interacts with AIP1/Alix and ALG-2 and modulates apoptosis in astrocytes. J.Biol.Chem. 275:19275-19281
3. Borinstein, S. C., Hyatt, M. A., Sykes, V. W., Straub, R. E., Lipkowitz, S., Boulter, J., and Bögler, O. (2000) SETA is a multifunctional adapter protein with three SH3 domains that binds Grb2, Cbl and the novel SB1 proteins Cellular Signalling 12:769-779
4. Schmidt, Mirko H. H., Chen, Baihua, Randazzo, Lisa M., and Bögler, O. (2003) SETA/CIN85/Ruk and its binding partner AIP1 associate with diverse cytoskeletal elements, including FAKs, and modulate cell adhesion J Cell Sci 116:2845
5. Schmidt, Mirko H. H., Furnari, Frank B., Cavenee, Webster K., and Bögler, O. (2003) Epidermal growth factor receptor signaling intensity determines intracellular protein interactions, ubiquitination, and internalization Proc.Natl.Acad.Sci.U.S.A 100:6505
6. Schmidt, M.H.H, Furnari, F.B., Cavenee, W.K., Dikic, I. and Bögler, O. (2004) Alix/AIP1 interacts constitutively with EGFR and antagonizes its downregulation by the Cbl-SETA/CIN85 complex. Mol. Cell Biol. 24(20):8981-8993.
7. Schmidt, M.H.H., Dikic, I. and Bögler, O. (2005) Src phosphorylation of Alix/AIP1 modulates its interaction with binding partners and antagonizes its activities. J. Biol. Chem. 280:3414-3425.
Analysis of the clinical potential of a new generation of platinum compounds and assessing the role of p53 in mediating response
We are interested in a new generation of platinum compounds, the BBR series, which show greater efficacy and lower toxicity than cisplatin. These compounds have been developed by Dr. Nick Farrell (VCU, Richmond, VA), a chemist developing novel platinum compounds. Clonogenic assays in culture and analysis of xenografts in mice have shown that BBR compounds are more potent than cisplatin in the killing of glioma cells. At concentrations that kill 90% of the cells in culture the BBR compounds effectively induce components of the MAPK signaling pathway. P53 mutants modulate the response of glioma cells to these compounds. Ongoing efforts focus on using genomics and proteomics to understand the differences in the cellular response to these drugs, and to generate profiles that may predict response.
Regulation of genomic DNA methylation by p53 and its role in glioma progression
In collaboration with Dr. Shirley Taylor at Virginia Commonwealth University we are analyzing the impact of p53 status on the response of normal and transformed glial cells to changes in DNA methylation status, as well as the regulation of the DNA methyl transferase genes by p53. We recently published the finding that p53 binds to the DNMT1 promoter and represses it, a novel mode for p53 transcriptional regulation, and an indication that the loss of wild-type p53 function may lead directly to aberrations in DNA methylation status [8].
8. Peterson, EJ, Bögler, O., and Taylor, SM (2003) P53-mediated Repression of DNA Methyltransferase 1 Expression by Specific DNA Binding. Cancer Res. 63(20):6579-82.
Depending on the student’s interests, a tutorial in my laboratory would provide experience with signal transduction focused on receptor tyrosine kinase signal attenuation, protemics for the discovery of markers of response to therapeutic intervention or analysis of the regulation of DNA methylation. Common to all these areas is an integrated molecular and cell biological approach, and a translational framework that emphasizes the clinical aspects of any study.
Program Affiliation: