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Ian J. Davis, MD, PhD
Assistant Professor

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Research Interest
Key words: Transcriptional regulation, oncogenes, cancer biology, chromatin Research interests

Transcriptional deregulation plays a critical role in the development of many cancers. Mechanisms that result in oncogenic transcriptional deregulation include alterations in the expression or structure of proteins that modulate transcription directly or through epigenetic modifications. Hematopoetic cancers and solid tumors (in particular sarcomas) frequently harbor recurrent and specific cytogenetic abnormalities such as chromosomal translocations and amplifications. In many of these cancers, the pathognomonic translocations involve genes that encode transcription factors. Translocations combine features of both native genes to generate unique fused (or chimeric) genes characterized by alterations in expression and structure. Although the importance of these gene fusions to cancer development has been clearly demonstrated, a fundamental understanding of how these changes mediate oncogenesis remains elusive.

Notable examples of translocation-associated transcription factor dysregulation include the MYC or MiT basic helix-loop-helix leucine zipper families which can be amplified or translocated in a wide range of cancers including lymphoma, neuroblastoma, melanoma, pediatric renal carcinoma and clear cell sarcoma. Similarly, ETS winged helix-turn-helix transcription factors and PAX3 or PAX7 paired box/homeodomain transcription factors are translocated in Ewing's sarcoma and alveolar rhabdomyosarcoma, respectively. In each case, the abnormal transcription factor plays central role in the oncogenic process.

While it is presumed that these deregulated transcription factors mediate oncogenesis by altering target gene expression, we lack a mechanistic understanding of how dysregulation modifies the activity of these transcription factors and their participation in transcriptional networks. Furthermore, in contrast to the success of chimeric kinase inhibition, the molecular attributes of transcription factors make them challenging candidates for therapeutic modulation by small molecules. Focusing on those classes of transcription factors strongly implicated in oncogenesis, our lab employs genomic and proteomic approaches to study transcription factor targeting and gene regulation in cancer and in normal development. Through the identification of oncogenic transcriptional mechanisms and relevant transcriptional targets, we hope to develop novel biologically based therapies for these cancers.

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Publications
Davis, I.J. and D.E. Fisher. 2007. MiT transcription factor associated malignancies in man. Cell Cycle. In press.

Tsuda M, Davis IJ, Argani P, Shukla N, McGill GC, Nagai M, Saito T, Lae M, Fisher DE, Ladanyi M. 2007. TFE3 fusions activate MET signaling by transcriptional upregulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer Research. 67, 919-29.

Davis I.J., J. J. Kim, F. Ozsolak, H.R. Widlund, O. Rozenblatt-Rosen, S.R. Granter, J. Du, J.A. Fletcher, C.T. Denney, S.L. Lessnick, W.M. Linehan, A.L. Kung and D.E. Fisher. 2006. Oncogenic MITF dysregulation in clear cell sarcoma: defining the MiT family of human cancers. Cancer Cell. 9, 473-484.

Mukohara, T., G. Civiello, I.J. Davis, M.L. Taffaro, J. Christensen, D.E. Fisher, B.E. Johnson and P.A. Jänne. 2005. Inhibition of the Met receptor in mesothelioma. Clinical Cancer Research. 11, 8122-8130.

Argani, P., M. Lae, B. Hutchinson, V.E. Reuter, M.H. Collins, J. Perentesis, J.E. Tomaszewski, J.S. Brooks, G. Acs, J.A. Bridge, S.O. Vargas, I.J. Davis, D.E. Fisher and M. Ladanyi. 2005. Renal Carcinomas With the t(6;11)(p21;q12): Clinicopathologic Features and Demonstration of the Specific Alpha-TFEB Gene Fusion by Immunohistochemistry, RT-PCR, and DNA PCR. American J. Surgical Pathology. 29, 230-240.

Miller, A.J., C. Levy, I.J. Davis, E. Razin and D.E. Fisher. 2005. SUMOylation of MITF and its related family members TFEB and TFE3. J Biological Chemistry. 280, 146-55.

Huber, W.E., R. Price, H.R. Widlund, J. Du, I.J. Davis, M. Wegner and D.E. Fisher. 2003. A tissue restricted cAMP transcriptional response: SOX10 modulates MSH-triggered expression of MITF in melanocytes. J. Biological Chemistry. 278, 45224-30.

Thornley, I., L. Lehmann, W.S. Ferguson, I. Davis, E.N. Forman and E.C. Guinan. 2003. Homozygous alpha-thalassemia treated with intrauterine transfusions and postnatal hematopoietic stem cell transplantation. Bone Marrow Transplant. 32:341-2.

Davis, I.J, B.-L. Hsi, J. Arroyo, S.O. Vargas, Y.A. Yeh, G. Motyckova, P. Valencia, A.R. Perez-Atayde, P. Argani, M. Ladanyi, J.A. Fletcher and D.E. Fisher. 2003. Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation.  Proceedings of the National Academy of Sciences. 100, 6051-6.
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Lineberger Comprehensive Cancer Center
21-244, CB# 7295
996-5360 (office) 996-4340 (lab) 996-8212 (fax)
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