Hospital for Sick Children
555 University Avenue
Toronto, Ontario M5G 1X8
Phone: 416-813-7654 ext. 302912
Email Dr. Meredith Irwin
P53 family signaling, chemosensitivity and neuroblastoma tumor initiating cells
Our lab is interested in pathways that regulate tumor cell death and chemosensitivity. We
have two main areas of focus including:
(1) p53 family protein signaling and (2) novel signaling pathways and therapeuticsaimed at neuroblastoma tumor initiating cells (TICs). P73 and p63 are two paraloguesof the p53 tumor suppressor protein. We previously discovered that p73 is inducedby chemotherapies and that the pro-apoptotic isoform (TAp73) mediates cell deathin response to chemotherapies and other anti-cancer agents. Our studieshave shown that p73 activity and stability is modulated by ubiquitination andneddylation and a current area of research involves elucidating the pathwaysthat regulate these post-translational modifications of p73 and p63 in cancerand human disease. A second line of study involves the identification of novelp73 and p63 binding partners. We found that SATB2 (special AT-rich binding partner-2) bindsto certain p63 and p73 isoforms regulating their ability to induce apoptosisin response to chemotherapy. Preliminary data demonstrates an exciting role forSATB2 in survival and metastases in certain solid tumors. We are also determiningthe role of other novel p73 and p63 interacting proteins identified in our screens.
Our lab is also interested in novel therapeutics for the pediatric cancer neuroblastoma. Our previous studies determined that cox inhibitors and the MDM2 antagonist nutlin induce apoptosis and enhance chemosensitivity in neuroblastoma via activation of p73 and p53. Recent studies are aimed at identifying novel survival pathways and therapeutics for neuroblastoma using TICs isolated from bone marrow metastases from our neuroblastoma patients. We are currently testing candidate therapies in vitro and in vivo.
List of Key Publications:Link to Pubmed Publications
Irwin MS, Kondo K, Marin MC, Cheng LS, Hahn WC, Kaelin WG Jr. Chemosensitivity linked to p73 function. Cancer Cell . 2003: 3;403-10.
Watson IR, Blanch A, Lin DCC, Ohh M, Irwin MS. MDM-2 mediated Nedd 8 modification of TA p73 Regulates its transactivation function. Journal of Biological Chemistry 2006: 281(45): 34096-103 .
Lau LM, Nugent-Wolter J, Zhao X, Irwin MS.HDM2 antagonist Nutlin-3 disrupts p73 HDM2 binding and enhances p73 function. Oncogene 2008: 27 (7): 997-1003.
Lau LMS, Nugent-Wolter JK, Lau JTML, Cheng LS, Smith KM, Hansford LM, Zhang L, Baruchel SB, Robinson F, and Irwin MS. Cox inhibitors differentially modulate pro and anti-apoptotic p73 isoforms in neuroblastoma. Oncogene , 2009: 28(19):2024-33
Chung JK, Lau JTML, Cheng LS, Grant RI, Robinson F, Ketela T, Pintor dos Reis P, Roche O, Moffat J, Kamel-Reid S, Ohh M, Perez-Ordonez B, Kaplan DR, Irwin MS. SATB2 augments DNp63a-mediated transrepression: implications for chemosensitivity 2010, EMBO Reports 2010: 11(10):777-83.
- Alex Seong
- Jennifer Wolter