Pathology

Pathophysiology and Signal Transduction
  • Associate Professor: Yusuke Ohba
  • Assistant Professor: Masumi Tsuda
  • Phone: +81-11-706-5158
  • FAX: +81-11-706-7877
  • E-mail: yohba
Intracellular signal transduction-process by which a cell converts a kind of stimulus into another-is implicated in a variety of biochemical reactions in both of pathological and physiological cellular events. Nowadays, the number of proteins and other molecules participating in the events involving signal transduction increases, resulting in a formation of "signaling network." Disruption of such highly organized networks causes the onset of diseases, including neoplasm. Therefore, a better comprehension of the signal network and its aberrant transformation in diseases will be a great help not only for the understanding of the molecular basis of diseases, but also for discovery of molecular targeted drugs and novel diagnostic technologies.

Research

The aim of our laboratory is to evaluate spatiotemporal dynamics of intracellular signaling in living cells, tissues, and organisms, and to characterize signal transduction pathways in cancerous cells to apply them to the diagnosis and therapeutics. To study signal transduction with spatiotemporal dynamics, we utilize biochemical, molecular biological, as well as bioimaging techniques, including fluorescent proteins (FPs) and Förster (fluorescence) resonance energy transfer (FRET). These technologies enable us to examine dynamic cellular events such as protein-protein interactions in living cells, and to evaluate the aberrant status of signaling and its reversion in responses to drugs by using living tumor cells originating each patient. We also develop novel imaging techniques for further-in-depth research to achieve our aims.
For instance, the world's first clinical application of FRET-based biosensors has been released from our laboratory (ref. 3). The biosensor allows a confident clinical decision to prescribe the most effective agent among molecular target drugs available for leukemia patients.
Tumor microenvironment is well known to be important for cancer progression as well as cancer cells themselves. We are developing a 3D culture system, in combination with fluorescence imaging, to visualize tumor cell-stromal cell interaction and provide in detail the molecular mechanisms through which tumor acquire malignant potentials.

Education

Faculty members in this section give classes of Pathology and Medical Research Practice for medical students; and also take part in the classes of Medical Research Courses for graduate students. Almost all of these classes are given in Japanese, while only a few are given in English. We accept applications of young prospective researchers who take master (2 years) or doctoral (4 years) courses to learn the signal transduction research in our laboratory.

Courses in English

Not available

Number of Students from Abroad

Current: None

Recent 5 years: None

Related Staff

  • Postdoctoral Fellow: Yoichiro Fujioka
  • Graduate Student: Ryuta Arai
  • Graduate Student: Akiko Kaneyasu
  • Graduate Student: Takanori Wagatsuma
  • Undergraduate Student: Takuma Kaibara
  • Technician: Noriko Toyoda
Fig1
1 Live cell imaging of Ras activation by FRET. Red and blue represent high and low Ras activities, respectively.
Fig2
Fig3
2 Schematic diagram of the relationship between EGFR and PTHrP signaling in Oral cancer. Activation of EGFR up-regulates PTHrP gene expression. PTHrP binds to PTH/PTHrP receptor (PTH1R), activating ERK and PI3-K/Akt, which, in turn, leads to enhanced cell proliferation, migration, and invasion.
3 Members of our laboratory.

International Activities

Recent invited talks

  • Ohba Y: Imaging of signal transduction pathways in living cells. Long Term Live Cell Imaging Workshop, Soul, Korea, 2006
  • Ohba Y: Imaging of signal transduction pathway in living cells. CMM-NUS Workshop on FRET, FLIM, FRAP and FCCS; techniques to measure cellular protein dynamics, Singapore, 2006
  • Ohba Y: Imaging of signal transduction pathways in living cells. Symposium, 2nd World Congress 2006

Selected Publications

1. Yamada T, Tsuda M, Takahashi T, Totsuka Y, Shindoh M, and Ohba Y (2011) RANKL expression specifically observed in vivo promotes epithelial mesenchymal transition and tumor progression. Am J Pathol 178: 2846-2857
2. Fujioka Y, Tsuda M, Hattori T, Sasaki J, Sasaki T, Miyazaki T, and Ohba Y (2007) 4. The Ras-PI3K Signaling Pathway Is Involved in Clathrin-Independent Endocytosis and the Internalization of Influenza Viruses. PLoS ONE 6: e16324
3. Mizutani T, Kondo T, Darmanin S, Tsuda M, Tanaka S, Tobiume M, Asaka M, and OhbaY (2010) A novel FRET-based biosensor for the measurement of BCR-ABL activity and its response to drugs in living cells. Clin Cancer Res 16: 3964-3975
4. Tsutsumi K, Fujioka Y, Tsuda M, Kawaguchi H, and Ohba Y (2009) Visualization of Ras-PI3K interaction in the endosome using BiFC. Cell Signal 21: 1672-1679
5. Inuzuka T, Tsuda M, Tanaka S, Kawaguchi H, Higashi Y, and Ohba Y (2009) Integral role of transcription factor 8 in the negative regulation of tumor angiogenesis. Cancer Res 69: 1678-1684