Peter Hurlin

Assistant Investigator - Shriners Hospitals for Children

Assistant Professor - Department of Cell and Developmental Biology

Myc proteins are normally required for cells to traverse the cell cycle, but when their expression is deregulated by mutations, gene amplification or chromosomal translocations, they promote uncontrolled cell proliferation, inhibit cell differentiation and contribute to tumorigenesis. The ability of Myc to bind DNA and function as a transcription factor is dependent on interaction with a protein called Max. Interaction between Myc and Max is mediated by a shared bHLHZip domain. We have identified a set of proteins related to Myc that also interact with Max. One of the primary goals of the our laboratory is to understand how these Myc-related proteins impinge on Myc functions associated with the control of proliferation and oncogenesis. The Mnt protein is one of the Myc-related proteins we are studying. Mnt appears to function as an antagonist to Myc since in cell culture experiments Mnt can suppress turmorigenic transformation by Myc. To gain insight into the biological function of Mnt we are analyzing mice that contain a targeted deletion in the mnt gene that creates a null allele. We are also using a conditional gene inactivation approach to examine the function of Mnt in specific tissues (e.g. regions of the brain and in B- and T-cells). Finally we are using cell strains derived from mice lacking Mnt to investigate Mnt functions associated with the control of cell proliferation and as a potential cellular antagonist of Myc. Another of the Myc-related proteins we have identified is Mga. Mga is a very unusual protein in that it has both a Myc-like bHLHZip domain and a T-domain. The T-domain is a highly conserved DNA-binding domain originally found in the protein Brachyury. Brachyury and other proteins that contain a T-domain function as key regulators of cell fate decisions (e.g. mesoderm induction, limb identity and specification etc.). We hypothesize that Mga functions to link the control of cell proliferation with the regulation of cell fate decisions. We are generating mice that contain a targeted deletion in the mga gene to examine its role in embryonic development and oncogenesis and using genetic and biochemical methods to examine transcriptional mechanisms that underly the biological activity of Mga. Finally, our laboratory seeks to understand the biological function of Tbx3, a T-domain protein that, when mutated, causes a plieomorphic syndrome in humans called ulnar-mammary syndrome. We are using cell culture systems and transgenic mice to test the hypothesis that Tbx3 effects cell fate decisions by regulating pathways controlling apoptosis and cellular senescence. We are also investigating mechanisms responsible for Tbx3 to function as a transcriptional repressor.

Hurlin, P. J., Qœeva, C. and Eisenman, R.N. Mnt, a Novel Max-Interacting Protein is Coexpressed with Myc in Proliferating Cells and Mediates Repression At Myc Binding Sites. Genes & Development 11:44-58, 1997.

Hurlin, P.J., Steingr’msson, E., Copeland, N. G., Jenkins, N. A. and Eisenman. R. N. Mga, a Dual-Specificity Transcription Factor that Interacts with Max and Contains a T-Domain DNA Binding Motif. EMBO J. 18:7019-28, 1999

Carlson, H., Ota, S. Campbell, C.E. and Hurlin, P.J. A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause Ulnar-Mammary syndrome. Human Molecular Genetics, 2001, in press

To contact Dr. Hurlin directly: pjh@shcc.org