Jonathan D Licht, MD
- ADJUNCT PROFESSOR | Medicine, Hematology and Medical Oncology
- ADJUNCT PROFESSOR | Cell, Developmental & Regenerative Biology
- ADJUNCT PROFESSOR | Oncological Sciences
Transcription Factors Disrupted In Human Cancer-Their Mechanism Of Action And Targets
The broad goal of my research program is to understand how mutations of
transcriptional regulators may set up patterns of aberrant gene
expression that yield cancer. This requires a detailed understanding of
the normal function of these transcription factors. Such information
includes an understanding of the role of these factors in cell growth,
differentiation and developmental, the normal DNA binding and
transcriptional activity of these proteins, identification of the
critical protein partners of the factors and elucidation of the
downstream targets of these genes. The mutations that occur in cancer
are tragic experiments of nature that may alter critical amino acid
residues for the function of the proteins. By modeling the function of
both the normal and mutated forms of these factors we hope to better
understand the molecular basis of cancer and potentially identify new
therapeutic targets and pathways in this disease.
Reciprocal signaling between the ureteric bud (UB -Green) and metanephric mesenchyme (Red) guides kidney development. Factors from the UB, including LIF and FGFs induce condensation of the mesenchyme and may induce the expression of factors like WT1 and Pax2 critical for epithelial differentiation. WT1 may induce the expression of growth factors like amphiregulin, Wnt4 and GDNF which stimulate the UB and mesenchyme. At the same time WT may induce the expression of sprouty a counter-regulatory factor THAT limits the effects of growth factor signaling on the condensing mesenchme.
Benezra M, Chevallier N, Morrison DJ, MacLachlan TK, El-Deiry WS, Licht JD. BRCA1 augments transcription by the NF-kappaB transcription factor by binding to the Rel domain of the p65/RelA subunit. J Biol Chem 2003 Jul 18; 278(29): 26333-26341.
McConnell MJ, Chevallier N, Berkofsky-Fessler W, Giltnane JM, Malani RB, Staudt LM, Licht JD. Growth suppression by acute promyelocytic leukemia-associated protein PLZF is mediated by repression of c-myc expression. Mol Cell Biol 2003 Dec; 23(24): 9375-9388.
Gross I, Morrison DJ, Hyink DP, Georgas K, English MA, Mericskay M, Hosono S, Sassoon D, Wilson PD, Little M, Licht JD. The receptor tyrosine kinase regulator Sprouty1 is a target of the tumor suppressor WT1 and important for kidney development. J Biol Chem 2003 Oct 17; 278(42): 41420-41430.
Ahmad KF, Melnick A, Lax S, Bouchard D, Liu J, Kiang CL, Mayer S, Takahashi S, Licht JD, Prive GG. Mechanism of SMRT corepressor recruitment by the BCL6 BTB domain. Mol Cell 2003 Dec; 12(6): 1551-1564.
Takahashi S, McConnell MJ, Harigae H, Kaku M, Sasaki T, Melnick AM, Licht JD. The Flt3 Internal Tandem Duplication Mutant Inhibits the Function of Transcriptional Repressors by Blocking Interactions with SMRT. Blood 2004 Feb 24 [Epub ahead of print];.
Chevallier N, Corcoran CM, Lennon C, Hyjek E, Chadburn A, Bardwell VJ, Licht JD, Melnick A. ETO protein of t(8;21) AML is a corepressor for Bcl-6 B-cell lymphoma oncoprotein. Blood 2004 Feb 15 ; 103(4): 1454-1463.
Mason JM, Morrison DJ, Bassit B, Dimri M, Band H, Licht JD, Gross I. Tyrosine Phosphorylation Of Sprouty Proteins Regulates Their Ability to Inhibit Growth Factor Signaling-A Dual Feedback Loop. Mol Biol Cell 2004 May; 15(5): 2176-2188.