Basic Medicine, Molecular and Cellular Biology
To Understand the Molecular Mechanisms Underlying Pathogenesis of GATA-factor-related Diseases; How Transcriptional Regulatory Network Governs Maintenance of Hematopoietic Homeostasis in Mammals
Health Sciences Course
- Master / Doctoral Degree
- SHIMIZU, Ritsuko
Professor, M.D. Ph.D.
rshimizu*med.tohoku.ac.jp (Please convert "*" into "@".)
- Research on the vital roles of transcription factors GATA1 and GATA2 during mammalian hematopoiesis
- Research on the mechanisms underlying pathogenesis of leukemias caused by quantitative and qualitative dysfunction in GATA factors
- Drug discovery research of GATA-factor-related diseases
regulation of gene expression, GATA factors, leukemias, drug discovery
gene editing in mice, fluorescent activated cell sorter, experimental hematological analysis; e.g. transplantation, colony assay, cell culture, high-throughput screening
In 1988, Prof. Weintraub identified MyoD as a key transcription factor that had a potential to directly reprogram fibroblasts to myocytes. Since then, a large number of scientists have rushed into cloning races of transcription factors that is vital for cell fate decision. In this process, GATA1 and GATA2 were identified as transcription factors indispensable for hematopoiesis.
GATA2 is expressed in hematopoietic stem/progenitors and important for maintenance of pluripotent stem cells, whereas GATA1 is mainly expressed in cells committed to erythroid and megakaryocytic lineages and requisite for differentiation, control of proliferation and cell survival. In 21 century, multiple cases of germline and somatic mutations on GATA1 and GATA2 genes have been discovered in humans suffering hematopoietic abnormalities/malignancies. However, it remains to be uncertain how the dysfunction of GATA factors contributes to the onset of the diseases. We are now challenging to clarify the molecular mechanisms on the pathogenesis of the hematopoietic diseases caused by quantitative and qualitative dysfunction of GATA factors, focusing on the vital roles of GATA1 and GATA2 in transcriptional regulatory network during mammalian hematopoiesis. Furthermore, we are interesting in drug discovery against diseases involving GATA factors.
Figure 1. Hematologic diseases caused by dysfunctions of GATA factors
Figure 2. Drug discovery targeting for GATA factors
- Shimizu R, Engel JD, Yamamoto M. GATA1-related leukemias. Nat Rev Cancer, 8(4):279-287, 2008
- Hasegawa A, et al. Mature erythrocyte membrane homeostasis is compromised by loss of the GATA1-FOG1 interaction. Blood, 119(11):2615-2623, 2012
- Kaneko H, et al. N- and C-terminal transactivation domains of GATA1 protein coordinate hematopoietic program. J Biol Chem, 287(25):21439-21449, 2012
- Toki T, et al. Naturally occurring oncogenic GATA1 mutants with internal deletions in transient abnormal myelopoiesis in Down syndrome. Blood. 121(16):3181-3184, 2013
- Yamazaki H, et al. A Remote GATA2 Hematopoietic Enhancer Drives Leukemogenesis in inv(3)(q21;q26) by Activating EVI1 Expression. Cancer Cell, 25(4) 415-427, 2014
- Hasegawa A. et al. GATAI binding kinetics on conformation-specific birding sites elicit differentiate transcriptional regulation. Mol Cell Biol 36(1), 2051-2067, 2016