Discovering

INDIVIDUAL RESEARCHER

Education

Current Research

 As a major mechanism whereby cells maintain homeostasis and genetic integrity, stress responses are mediated by transcription factors that are often convergence points for many signaling pathways.  The contribution of these stress-related transcription factors to cell-fate determination often extends beyond transcriptional regulation to include changes in cellular functions through protein-protein interaction networks.  One of our major research interests is ATF3 (activating transcription factor 3), a member of the ATF/CREB family of transcription factors which is rapidly induced by a large variety of cellular stresses (e.g., DNA damage).  We have demonstrated that ATF3, via its basic Leucine Zipper (bZip) domain, interacts with the tumor suppressor p53 and MDM2, the major p53 repressor, and consequently stimulates p53 function upon DNA damage by blocking ubiquitin-mediated p53 degradation. Moreover, we have found that ATF3 antagonizes the tumor-promoting activity of the E6 protein of human papilloma virus by binding to the viral protein.  These findings, in combination with the observations that ATF3 is aberrantly expressed in many human cancers, suggest that ATF3, as a stress sensor, may be a novel tumor suppressor protein. Accordingly, one goal of our research is to elucidate the roles of ATF3 in regulating the p53 pathway and tumorigenesis using both in vitro approaches and genetically-engineered mouse models.  We are interested in further characterization of the ATF3-interaction network in order to gain a better understanding of ATF3 functions in cellular responses to DNA damage and other stresses.  Ultimately, such knowledge will allow us to develop prophylactic or therapeutic strategies to restore normal stress responses. In addition, as an initial effort to seek novel cancer therapeutics, we are also utilizing genetic-engineering approaches to develop cell-based, high-throughput screening assays for identification of small-molecule p53 activators that can inhibit expression of major p53 repressors.  Such a study will provide a proof of concept for an innovative strategy that can be applied to discover novel anti-cancer drugs targeting the “undruggable” targets, i.e., aberrant gene expression wide-spread in cancer.

PubMed Publications

1. Wang H, Yan C. (2011) A small-molecule p53 activator induces apoptosis through inhibiting MDMX expression in breast cancer cells. Neoplasia 13:611-619.



2. Wang H, Ma X, Ren S, Buolamwini JK, Yan C. (2011) A small-molecule inhibitor of MDMX activates p53 and induces apoptosis. Mol. Cancer Ther. 10:69-79.



3. Yan C. (2010) Post-translational modification of p53 by ubiquitin. Methods Mol. Biol. 647:305-315.



4. Mo P, Wang H, Lu H, Boyd DD, Yan C. (2010) MDM2 mediates ubiquitination and degradation of activating transcription factor 3. J. Biol. Chem. 285:26908-26915.



5. Wang H, Mo P, Ren S, Yan C. (2010) Activating transcription factor 3 activates p53 by preventing E-associated protein from binding to E6. J. Biol. Chem. 285:13201-13210.



6. Nair RR, Avila H, Ma X, Wang Z, Lennartz M, Darnay BG, Boyd DD, Yan C. (2008) A novel high-throughput screening system identifies a small molecule repressive for matrix metalloproteinase-9-expression. Mol. Pharmacol. 73:919-929