Rainer Brachmann
M.D., Ludwig-Maximilians-Universität, München, Germany, 1987
Department of Medicine
Division of Hematology/Oncology
University of California, Irvine
Irvine, CA 92697
Office: (949) 824-8778
Lab: (949) 824-8456
rbrachma@uci.edu
Research Interests:
Cancer genetics, chromatin & transcriptional regulation, tumor suppressor gene p53
The tumor suppressor protein p53 plays a central role in protecting humans from cancer. It does so mainly as a transcription factor that induces cell cycle arrest, DNA repair and/or apoptosis after one of several stress signals has led to its activation. Close to half of all human cancers carry missense mutations in the p53 gene. p53 mutant proteins do not drive the MDM2 negative feedback loop and are therefore present at abnormally high levels in cancer cells.
Restoring wild-type function to this vast pool of p53 mutant protein would have a significant impact on anti-cancer therapy. Toward this goal, we have identified a general "suppressor motif" comprising codons 235, 239 and 240 that, in the context of the same protein, restores function to more than half of the most common p53 cancer mutants. We are now determining the structure of several of these p53 mutants in collaboration with a crystallography laboratory. This will provide the framework for the design of small molecules able to stabilize p53 mutants which can then be tested as anti-cancer therapies.
It is very likely that cancers with wild-type p53 have inactivated the p53 pathway by other means. There are two clear examples of direct p53 inactivation in human cancers for which the exact molecular mechanism remains unclear: nuclear stabilization and inactivation (found in testicular cancers) and cytoplasmic sequestration (found in breast and colon cancers, as well as neuroblastomas). We tackle these two questions by using a yeast p53 dissociator assay that selects for candidate proteins that may play a role in these types of p53 inactivation.
The yeast p53 dissociator assay has also allowed us to isolate proteins that in human cells are likely mediators of p53 function or which are negatively regulated by p53. We are now investigating several of these proteins in mammalian assays. One particular focus is the further characterization of hADA3, a protein that is part of histone acetyltransferase complexes and that is required for p53 transcriptional activity.
Selected Publications:
Dearth, L.R., Qian, H., Wang, T., Baroni, T.E., and Brachmann, R.K. p53 cancer mutants show complex patterns of loss-of-function, interference with wild-type p53 and subcellular localization (submitted).
Brachmann, R.K. (2004). p53 mutants --- the Achilles' heel of human cancers? Cell Cycle 3 (8), 1030-1034.
Dearth, L.R. and Brachmann, R.K. (2004). ATP, cancer and p53. Cancer Biology and Therapy, 3 (7), 638-640.
Baroni, T.E., Wang, T., Qian, H., Dearth, L.R., Truong, L.N., Zeng, J., Denes, A.E., Chen, S.W.-Y., and Brachmann, R.K. (2004) A global suppressor motif for p53 cancer mutants. PNAS 101, 4930-4935.
Davis, P.K., and Brachmann, R.K. (2003). Chromatin remodeling and cancer. Cancer Biology & Therapy 2, 22-29.
Kobayashi, T., Wang, T., Qian, H., and Brachmann, R.K. (2003). Genetic strategies in Saccharomyces cerevisiae to study human tumor suppressor genes. In Methods in Molecular Biology, vol. 223: Tumor suppressor genes: regulation, function, and medicinal applications. W.S. El-Deiry, ed. (Totowa, NJ: Humana Press), 73-86.
Qian, H., Wang, T., Naumovski, L., Lopez, C.D., and Brachmann, R.K. (2002). Groups of p53 target genes involved in specific p53 downstream effects cluster into different classes of DNA binding sites. Oncogene 21, 7901-7911.
Wang, T., Kobayashi, T., Takimoto, R., Denes, A.E., Snyder, E.L., El-Deiry,W.S., and Brachmann, R.K. (2001). hADA3 is required for p53 activity. EMBO J. 20, 6404-6413.
Brachmann, R.K., Yu, K., Eby, Y., Pavletich, N.P., and Boeke, J.D. (1998). Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations. EMBO J. 17, 1847-1859.
Vidal, M., Brachmann, R.K., Fattaey, A., Harlow, E., and Boeke, J.D. (1996). Reverse two-hybrid and one-hybrid systems to detect dissociation of protein-protein and DNA-protein interactions. Proc. Natl. Acad. Sci. USA 93, 10315-10320.
Brachmann, R.K., Vidal, M., and Boeke, J.D. (1996). Dominant-negative p53 mutations selected in yeast hit cancer hot spots. Proc. Natl. Acad. Sci. USA 93, 4091-4095.
Brachmann, R., Lindquist, P.B., Nagashima, M., Kohr, W., Lipari, T., Napier, M., and Derynck, R. (1989). Transmembrane TGF-a precursors activate EGF/TGF-alpha receptors. Cell 56, 691-700.
