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 therapeutics aimed at neuroblastoma tumor initiating cells (TICs). P73 and p63 are two paralogues of the p53 tumor suppressor protein. We previously discovered that p73 is induced by chemotherapies and that the pro-apoptotic isoform (TAp73) mediates cell death in response to chemotherapies and other anti-cancer agents.  Our studies have shown that p73 activity and stability is modulated by ubiquitination and neddylation and a current area of research involves elucidating the pathways that regulate these post-translational modifications of p73 and p63 in cancer and human disease. A second line of study involves the identification of novel p73 and p63 binding partners. We found that SATB2 (special AT-rich binding partner-2)  binds to certain p63 and p73 isoforms regulating their ability to induce apoptosis in response to chemotherapy. Preliminary data demonstrates an exciting role for SATB2 in survival and metastases in certain solid tumors. We are also determining the 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.

Graduate Students:

• Alex Seong
• Jennifer Wolter

Selected References:

• 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.