Ph.D., University of California, Irvine, 1997
Cancer; development; aging; senescence; epigenetics, autism
Genetic pathways are precisely executed during embryogenesis but can become perturbed in the adult, leading to cancer and aging. We are identifying the genetic players in these processes and determining how their aberrant roles culminate in human disease.
Genomic analyses have revealed that human chromosome 1p36 is frequently deleted in neural, epithelial, and hematopoietic malignancies, indicating that this region harbors a tumor suppressor. However, this gene has remained elusive for three decades. We took a functional approach to identify a 1p36 tumor suppressor. Using chromosome engineering—a Cre/loxP based system—we created mice with gains and losses of regions of the mouse genome that corresponds to human 1p36. This enabled us to identify a potent tumor suppressive interval. Loss of this region predisposes to cancer, whereas gain of this region results in excessive tumor suppression (see figure 1). We next identified Chd5 as the tumor suppressor within the region, and determined that the encoded chromatin remodeling protein Chd5 regulates a tumor suppressive network including p19/p53- and p16/Rb-mediated pathways. The epigenetic role of Chd5 in development, cancer, and stem cell maintenance is currently being investigated.
The p63 Gene
Using a variety of p63 mouse models, we determined that deficiency of the p53-related protein p63 causes developmental defects, protects from tumorigenesis, triggers cellular senescence, and leads to accelerated aging in vivo. These findings indicate that cellular senescence provides tumor suppression at the expense of compromising tissue homeostasis. We are currently investigating how p63 regulates senescence and how this impacts cancer and aging.
Keyes, W.M., Pecorasro, M., Aranda, V., Vernersson-Lindahl, E., Li, W., Vogel, H., Guo, X., Garcia, E.M., Michurina, T.V., Enikolopov, G., Muthuswamy, S.K., and Mills, A.A. 2011. DeltaNp63alpha is an oncogene that targets chromatin remodeler Lsh to drive skin stem cell proliferation and tumorigenesis. Cell Stem Cell 2: 164–176.
Mills, A.A. 2010. Throwing the cancer switch: reciprocal roles of polycomb and trithorax proteins. Nat. Rev. Cancer 10: 669–682.
Guo, X., Keyes, W.M., Papazoglu, C., Zuber, J., Li W., Lowe, S.W., Vogel, H., and Mills, A.A. 2009. TAp63 induces senescence and suppresses tumorigenesis in vivo. Nature Cell Biol. 11: 1451–1457.
Bagchi, A., and Mills, A.A. 2008. The quest for the 1p36 tumor suppressor. Cancer Research 68: 2551–2556.Bagchi, A., Papazoglu, C., Wu, Y., Capurso, D., Brodt, M., Francis, D., Bredel, M., Vogel, H., and Mills, A.A. 2007. CHD5 is a tumor suppressor at human 1p36. Cell 128: 459–475.