Geoffrey Wahl
e-mail: wahl@salk.edu |
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The Wahl Lab is studying the genetic basis of the origin and progression of cancer and why tumors become resistant to drugs. The underlying mechanisms of the genetic instability of cancer cells, and of their ability to develop resistance to anti-cancer drugs have remained a mystery to cancer biologists for the better part of a century. The Wahl Lab has found evidence that the instability derives from mutations in key genes that determine when it is safe for the cell to begin the important process of duplication of the genetic material. Such mutations also prevent cancer cells from responding to treatments commonly used in therapy that produce DNA damage, such as ionizing radiation. This increases the chances that a mutant cell will be produced every time it tries to reproduce itself. While this gives cancer cells many advantages for growth under stressful conditions, it also provides novel routes for the development of new anti-cancer therapies. The lab is now investigating how p53 is regulated, as 50% of human cancers express wild type p53 that is functionally compromised. Their efforts center on the use of in vitro systems and genetically modified mice to understand the contributions of two related proteins, Mdm2 and Mdm4 (Mdmx) to p53 regulation. Previous studies have shown that these proteins are essential for controlling p53 activity, and that they are frequently over- expressed in cancer cells as a way to mitigate p53 function in tumors containing wild type p53 genes. A goal of these studies is to develop drugs that antagonize Mdm2 and Mdmx to treat patients when tumors over-express these proteins. Another area of investigation concerns the identification and isolation of stem cells that are required to form each of the different types of cells in organs such as the mammary gland. This is important as the special properties of such cells, including their abilities to self-renew and to divide infrequently may enable them to contribute to cancer formation and to drug resistance.
Stommel, J., and Wahl, G.M. (2005) A new twist in the feedback loop: stress-activated MDM2 destabilization is required for p53 activation. (Invited Chapter). Cell Cycle 4 (3): 411-417.
Wong, E-T., Kolman, J.L., Li, Y-C., and Wahl, G.M. (2005) Reproducible doxycycline-inducible transgene expression at specific loci generated by Cre-recombinase mediated cassette exchange. Nucleic Acid Research. 33 (17) : e147.
Wahl, G.M., Stommel, J.M., Krummel, K.A., and Wade, M. (2005) Gatekeepers of the guardian: p53 regulation by post-translational modification, mdm2 and mdmx. "25 Years of p53 Research". Editors: Klas Wiman and Pierre Hainaut. Publisher: Springer. Chapter 4: 73-113. Printed in the Netherlands.
Nistér, M., Tang, M. , Zhang, X-Q., Yin, C., Beeche, M., Hu, X., Enblad, G., Van Dyke, T., and Wahl, G.M. (2005) p53 must be competent for transcriptional regulation to suppress tumor formation. Oncogene 24: 3563-3573.
Stommel, J. and Wahl, G.M. (2004) Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation EMBO Journal. 23: 1547-1556.
Vafa, O., Wade, M., Hampton, G.M., Pandita, T.K., and Wahl, G.M. (2002) Activated c-Myc induces DNA damage, increases reactive oxygebs species, and mitigates p53 function: a mechanism for oncogene induced genetic instability Mol. Cell 9: 1031-1044.
Wahl, G.M. and Carr, A. M. (2001) The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nature Cell Biol. 3: E277-E28.
Geoffrey M. Wahl received his Ph.D. from Harvard University and completed a postdoctoral fellowship at Stanford University. He serves on the editorial board of Molecular and Cellular Biology. He currently is a Professor in the Gene Expression Laboratory at the Salk Institute. He is also the President-elect of the American Association for Cancer Research.
