Molecular Pathology Group
Section leader
Kohei Miyazono (Guest Professor)
miyazono-ind(AT)umin.ac.jp
Eleftheria Vasilaki (Post-doc)
Coworkers
Daizo Koinuma (Lecturer at U. Tokyo)
Masato Morikawa (Graduate Student at U. Tokyo)
We are interested in how TGF-beta family members control gene expression profiles and cellular phenotypes. TGF-beta family members play critical roles in development and maintenance of tissue homeostasis. Signals transduced by TGF-beta family members regulate a wide variety of cellular processes, including differentiation, proliferation, migration and cell death in a cell-type specific and context-dependent manner. They are tightly regulated at several levels. Perturbations of the signaling pathways are implicated in a wide range of developmental disorders and diseases, including fibrotic disorders, autoimmune diseases, cardiovascular diseases and cancer. Our aim is to reveal the molecular mechanism and cellular functions of the TGF-beta family signaling pathways, which will help to understand the pathogenesis of the human diseases. We are also interested in identification of appropriate targets for new and more specific therapies.
ChIP-chip/ChIP-sequencing project
The cellular responses to TGF-beta family members depend upon cell types and the context. Because the DNA-binding affinities of the Smad transcription factors are relatively low, they interact with other DNA binding cofactors and cooperatively regulate a synexpression group of target genes. It is now widely accepted that the availability of cofactors explains, at least to some extent, how Smad complexes recognize their target sites.
Chromatin immunoprecipitation coupled with promoter array analysis (ChIP-chip) and ChIP followed by sequencing (ChIP-seq) have become a powerful tool to analyze genome-wide mapping of protein binding sites and epigenetic marks. We recently analyzed genome-wide binding profiles of Smad2/3 and Smad4 in HaCaT keratinocytes and identified that ETS1 and TFAP2A were important cofactors for Smads (Koinuma et al. 2009a, 2009b). ETS1 positively and TFAP2A negatively modulate the CDKN1A (p21CIP1) induction and cytostasis by TGF-beta. In our current work, we continue to examine the mapping data in order to characterize other transcription factors and cytokines which play important roles in TGF-beta-mediated transcriptional and cellular responses.
Angiogenesis project
Angiogenesis, the formation of new blood vessels from the pre-existing ones, is a fundamental process that plays critical roles in development and maintenance of tissue homeostasis throughout the life. It is also related to cancer progression and metastasis. Activin receptor-like kinase 1 (ACVRL1, also known as ALK-1) is an endothelial cell-specific type I receptor of the TGF-beta family. Heterozygous mutations in ACVRL1 are the cause of hereditary hemorrhagic telangiectasia (HHT), a multisystemic vascular disorder characterized by epistaxis (nose bleeds), telangiectasia and arteriovenous malformation (AVM).
We have identified several novel direct target genes of ALK-1 signaling and found that some of them play an important role during sprouting angiogenesis in vitro. We are now collaborating with the group of Dr. Johan Ledin at the EBC of Uppsala University to reveal the in vivo relevance of our findings using the zebrafish angiogenesis model.
The work is in close cooperation with the Subdepartment of Animal Evolution and Development, Department of Physiology and Developmental Biology, Evolutionary Biology Centre (EBC), Uppsala University, Genome Science Division, Research Center for Advanced Science and Technology (RCAST), University of Tokyo, and Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, and the TGF-beta Signaling group, the Protein Structure group and the Cancer Signals group at LICR.
| Selected Publications | |
| Publications 2009-2010 (see also annual reports) | |
| Ikushima, H., and Miyazono, K. (2010). TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer. 10, 415-424. | |
| Miyazono, K., Kamiya, Y., and Morikawa, M. (2010). Bone morphogenetic protein receptors and signal transduction. J Biochem. 147, 35-51. | |
| Koinuma, D., Tsutsumi, S., Kamimura, N., Imamura, T., Aburatani, H., and Miyazono, K. (2009a). Promoter-wide analysis of Smad4 binding sites in human epithelial cells. Cancer Sci. 100, 2133-2142. | |
| Koinuma, D., Tsutsumi, S., Kamimura, N., Taniguchi, H., Miyazawa, K., Sunamura, M., Imamura, T., Miyazono, K., and Aburatani, H. (2009b). Chromatin immunoprecipitation on microarray analysis of Smad2/3 binding sites reveals roles of ETS1 and TFAP2A in transforming growth factor beta signaling. Mol Cell Biol. 29, 172-186. | |