Laura GillespieProfessor of Molecular Oncology B.Sc., Ph.D. Ottawa
Terry Fox Cancer Research Laboratories Division of BioMedical Sciences Faculty of Medicine Memorial University of Newfoundland St. John’s, NL, Canada A1B 3V6
The MIER family of transcriptional regulators and their role in cell differentiation and cancer progression
The central theme of my research program is to define how specific sets of genes (gene programs) are coordinately regulated at the molecular level to produce a particular cellular response, whether it be to differentiate, to proliferate or to migrate.
Polypeptide growth factors are known to be involved in many of these cellular activities. Furthermore, it has become apparent that many of the known oncogenes are growth factors, their cellular receptors or components of their intracellular signaling pathways. Thus, elucidation of the regulatory mechanisms governing the cellular response to growth factors will further our understanding of how misregulation can lead to cancer.
Our work on fibroblast growth factor (FGF)-regulated cell differentiation led to the discovery of a novel transcription/chromatin regulatory molecule called Mesoderm Induction Early Response 1 (MIER1)1-3. We have since determined that one of its isoforms, MIER1α, specifically interacts with estrogen receptora (ERα) and represses its transcriptional activity4. Moreover, MIER1α is a powerful inhibitor of estrogen-stimulated growth of breast carcinoma cells4, demonstrating that it has the potential to play a critical role in the development and progression of breast cancer5. The current research in my lab is focused on elucidating the molecular aspects of MIER1α function and its link to breast cancer progression.
Two additional family members have now been identified: mier2 and mier3. Little is known about the proteins encoded by these 2 genes however our initial studies support the idea that MIER2 and MIER3 also have vital roles in transcriptional regulation6. Currently, my lab is investigating their function by characterizing the MIER2 and MIER3 transcriptional regulatory complexes, as a first step towards elucidating their molecular, cellular and physiological functions.
|This work is supported by research grants from the Faculty of Medicine Medical Research Fund (MRF) and the Natural Sciences and Engineering Research Council (NSERC) of Canada.|
1. Gillespie, L.L. and G.D. Paterno U.S. Patent No. 6746867, issued June 8, 2004.
2. Ding, Z., Gillespie, L. L. and G. D. Paterno 2003 Human MI-ER1 alpha and beta function as transcriptional repressors by recruitment of HDAC1 to their conserved ELM2 domain. Mol. Cell. Biol. 23: 250-258.
3. Ding, Z., Gillespie, L. L. and G. D. Paterno 2004 The SANT domain of hMI-ER1 interacts with Sp1 to interfere with GC box recognition and repress transcription. J. Biol. Chem. 279: 28009-28016.
4. McCarthy, P.L., Mercer, F.C., Savicky, M.W.J., Carter, B.A. Paterno, G.D. and L.L. Gillespie 2008 Changes in subcellular localization of MI-ER1a, a novel estrogen receptor-a interacting protein, is associated with breast cancer progression. Br. J. Cancer, 99, 639-646.
5. Li, S. Paterno, G.D. and L.L. Gillespie 2013 Nuclear Localization of the Transcriptional Regulator MIER1a Requires Interaction with HDAC1/2 in Breast Cancer Cells. PLoS ONE 8(12): e84046.
6. Derwish, R., Paterno, G.D. and L.L. Gillespie 2017 Differential HDAC1 and 2 recruitment by members of the MIER family. PLoS ONE 12(1): e0169338.