Yang Xu
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Our laboratory is interested in understanding the signaling pathways involved in maintaining genetic stability in mammalian cells, particularly embryonic stem cells. We are focusing on the roles of tumor suppressors such as ATM and p53, which are critical to maintain genetic stability. We are investigating the ATM kinase-mediated cellular responses to DNA strand-break damage. In addition, we are interested in the physiological roles of posttranslational modifications of p53 in regulating p53-dependent tumor suppression and aging.
p53 plays critical roles in tumor suppression and loss of p53 function is required for cancer progression. Consistent with this notion, p53 is the most commonly mutated tumor suppressor in human cancers. The majority of the p53 cancer mutations are missense mutation, leading to the expression of the full-length mutant p53. It has been known for many years that the expression of p53 mutants is associated with the poor prognosis of cancer patients. In this context, p53 mutants not only lose the tumor suppression activities, but also gain novel oncogenic activities to promote cancer progression and drug resistance. Therefore, it is critical to elucidate the gain of functions of p53 cancer mutants. Our recent findings that p53 cancer mutants induce genetic instability by inactivating ATM could have profound impacts on current cancer therapy. We will continue to elucidate the gain of function of p53 cancer mutants in promoting tumorigenesis.
Embryonic stem cells (ESCs) can undergo unlimited self-renewal while maintain their pluripotency to differentiate into all cell lineages in the body. Therefore, it is critical for ESCs to develop stringent mechanism to safeguard the genetic integrity so that DNA damage will not be passed on to progeny. We are investigating the pathways that coordinate the DNA damage responses and self-renewal of ESCs and adult stem cells. We are studying the hypothesis that disruption of this coordination will induce genetic instability in adult stem cell population, leading to the generation of cancer stem cells.
Recent publications (2005-present)
Xu, Y. Induction of genetic instability by p53 cancer mutants. Oncogene, in press.
Song, H. and Xu, Y. (2007). Gain of function of p53 cancer mutants in disrupting critical DNA damage response pathways. Cell Cycle 6: 1570-1573.Song, H., Hollstein, M. and Xu, Y. (2007). p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM. Nat. Cell. Biol. 9:573-580.
Chao, C., Wu, Z., Mazur, SJ, Borges, H., Rossi, M., Lin, T., Wang, JYJ, Anderson, CW, Appella, E and Xu, Y. (2006). Acetylation of Mouse p53 at Lysine 317 Negatively Regulates p53 Apoptotic Activities after DNA Damage. Mol. Cell. Biol. 26: 6859-69.
Chao, C., Herr, D., Chun, J. and Xu, Y. (2006). Phosphorylation of p53 at Ser18 and 23 is required for p53-dependent apoptosis and tumor suppression in aging animals. EMBO J. 25: 2615-22.
Xu, Y. (2006). DNA damage: a trigger of innate immunity but essential for adaptive immune homeostasis. Nature Reviews Immunology, 6:261-70.
Feng, L. Hollstein, M and Xu, Y. (2006). Ser46 phosphorylation regulates p53-dependent apoptosis and cellular senescence. Cell Cycle, 5(23): 2812-9.
Inlay, M.A., Gao,H., Lin, T., and Xu, Y. (2006). Critical roles of the immunoglobulin heavy and kappa light chain intronic enhancers in maintaining the sequential rearrangement of immunoglobulin loci. J. Exp. Med. 203:1721-32.
Inlay, M.A, Gao, H., Odegard, V.H., Lin, T., Schatz, D.G. and Xu, Y. (2006). Roles of the immunoglobulin kappa light chain intronic and 3’ enhancers in Igk somatic hypermutation. J. Immunol. 177:1146-51.
Xu, Y. (2005). A New Role for p53 in Maintaining Genetic Stability in Embryonic Stem Cells. Cell Cycle 4: 3-4.
Lin, T., Chao, C., Saito, S., Murphy, M., Appella, E. and Xu, Y. (2005). p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat. Cell Biol. 7: 165-171.
Feng, L., Lin, T., Uranishi, H., Gu, W. and Xu, Y. (2005). Functional analysis of the posttranslational modifications at p53 C-terminus in regulating p53 stability and activity. Mol. Cell. Biol. 25:5389-5395.
Kang, J., Ferguson, D., Bassing, C., Eckersdorff, M., Alt, F.W. and Xu, Y. (2005). Functional interaction of H2AX, NBS1 and p53 in ATM-dependent DNA damage responses and tumor suppression. Mol. Cell. Biol. 25: 661-670.
Yang Xu received his Ph.D. from Harvard University. He conducted postdoctoral research at the Massachusetts Institute of Technology as a fellow of the Damon Runyon-Walter Winchell Cancer Research Fund.
