Organization and Research

tanaka laboratory

 

Associate Professor
Kozo TANAKA, MD, PhD
Postdoctoral Fellow
Go ITOH, PhD

Research Project

Mechanisms of mitotic regulation in relation to oncogenesis and anti-cancer therapy

Normal human cells contain 46 chromosomes. In contrast, many cancer cells contain abnormal numbers of chromosomes (aneuploidy), and this is thought to be closely related to oncogenesis. In most cases, aneuploidy occurs through chromosome missegregation during mitotic phase. In mitotic phase, replicated chromosome pairs (sister chromatids) segregate to the two daughter cells by being pulled towards the spindle poles by microtubules (Fig. 1). Control mechanisms exist to ensure proper chromosome segregation, such as the spindle checkpoint, which is the mechanism that halts the progression of chromosome segregation until all sister chromatids attach to microtubules. It is probable that various other, as yet uncharacterised mechanisms are involved in ensuring proper chromosome segregation, and it is likely that defects in these mechanisms will result in chromosome missegregation. On the other hand, the mitotic phase is the time when many anti-cancer drugs show their effects on tumour cells. Anti-cancer drugs like the vinca alkaloids and taxol are widely used for the treatment of various cancers such as malignant lymphoma and breast cancer. These drugs prevent proper attachment of chromosomes to microtubules and thus activate spindle checkpoint (Fig. 2). Sustained spindle checkpoint activation is thought to induce cells to die, although the mechanism by which this occurs is largely unknown.
As mentioned above, elucidating mechanisms of mitotic regulation is important not only for understanding the mechanisms of oncogenesis, but also for improving anti-cancer therapy. Therefore, we will focus on the mitotic phase and investigate 1) the mechanism of chromosome missegregation, and 2) the mechanism of cell death by anti-mitotic drugs. The aim of this study is to contribute to the elucidation of mechanisms of oncogenesis and resistance to anti-cancer drugs, prediction of drug effects on individual patients, and modification of drug effects.

We are doing research using budding yeast (Saccharomyces cerevisiae) and human cells. Many genes involved in mitotic regulation are conserved between human and yeast cells. We can utilize amenable genetics in yeast, and can follow chromosome motion by observing live cells under fluorescence microscope. For example, Kozo Tanaka and colleagues observed the process of chromosome capture and transport by microtubules towards spindle poles and elucidated the mechanisms of this process in Tomoyuki U. Tanaka lab in University of Dundee, UK (Fig. 3, Tanaka et al. Nature (2005) 434, p987-994). On the other hand, human cells have more complicated mechanisms of mitotic regulation compared with yeast, and partial defects in the fine control mechanisms may lead to oncogenesis. We are intensively studying chromosome segregation process in human cells using various techniques, like fluorescence microscopy (Fig. 4), gene knockdown by RNAi, and proteome analysis. Thus, we are aiming to find new mechanisms of mitotic regulation by taking advantage of using both budding yeast and human cells.

Fig.1 (Click for large image.)
Fig.2 (Click for large image.)
Fig.3 (Click for large image.)
Fig.4 (Click for large image.)

Original articles (2004~)

  1. Endo, K, Mizuguchi, M, Harata, A, Itoh, G, and Tanaka, K. Nocodazole induces mitotic cell death with apoptotic-like features in Saccharomyces cerevisiae. FEBS Lett, (2010) in press.
  2. Kitamura, E*, Tanaka, K*, Komoto, S* (*equally contributors), Kitamura, Y, Antony, C, and Tanaka, T, U. Kinetochores generate microtubules with distal plus ends: their roles and limited lifetime in mitosis. Dev Cell, (2010) 18, p248-259.
  3. Sarai, N, Kagawa, W, Fujikawa, N, Saito, K, Hikiba, J, Tanaka, K, Miyagawa, K, Kurumizaka, H, and Yokoyama, S. Biochemical analysis of the N-terminal domain of human RAD54B. Nucleic Acids Res (2008) 36, p5441-5450.
  4. Romao, M, Tanaka, K, Sibarita J, B, Ly-Hartig, N, T, Tanaka, T, U, and Antony, C. Three-dimensional electron microscopy analysis of ndc10-1 mutant reveals an aberrant organization of the mitotic spindle and spindle pole defects in Saccharomyces cerevisiae. J Struct Biol (2008) 163, p18-28.
  5. Kitamura, E, Tanaka, K, Kitamura, Y, and Tanaka, T, U. Kinetochore-microtubule interaction during S phase in Saccharomyces cerevisiae. Genes Dev (2007) 21, p3319-3330.
  6. Tanaka, K, Kitamura, E, Kitamura, Y, and Tanaka, T, U. Molecular mechanisms of microtubule-dependent kinetochore transport towards spindle poles. J Cell Biol (2007) 178, p269-281.
  7. Valga, V, Helenius, J, Tanaka, K, Hyman A, A, Tanaka, T, U, and Howard J. Yeast kinesin-8 depolymerizes microtubules in a length-dependent manner. Nat Cell Biol (2006) 8, p957-962.
  8. Sarai, N, Kagawa, W, Kinebuchi, T, Kagawa, A, Tanaka, K, Miyagawa, K, Ikawa, S, Shibata, T, Kurumizaka, H, and Yokoyama, S. Stimulation of Dmc1-mediated DNA Strand Exchange by the Human Rad54B Protein. Nucleic Acids Res (2006) 34, p4429-4437.
  9. Tanaka, K, Mukae, N, Dewar, H, van Breugel, M, James, E, K, Prescott, A, R, Antony, C, and Tanaka, T, U. Molecular mechanisms for kinetochore capture by spindle microtubules. Nature (2005) 434, p987-994.
  10. Dewar, H, Tanaka, K, Nasmyth, K, and Tanaka, T, U. Tension between two kinetochores suffices for their bi-orientation on the mitotic spindle. Nature (2004) 428, p93-97.
  11. Kinebuchi, T, Kagawa, W, Enomoto, R, Tanaka, K, Miyagawa, K, Shibata, T, Kurumizaka, H, and Yokoyama, S. Structural basis for octameric ring formation and DNA interaction of the human homologous-pairing protein Dmc1. Mol Cell (2004) 14, p363-374.

Review articles

  1. Tanaka, K, Kitamura, E, and Tanaka, T, U. Live cell analysis of kinetochore-microtubules interaction in budding yeast. Methods in press.
  2. Tanaka, K, and Tanaka, T, U. Live cell imaging of kinetochore capture by microtubules in budding yeast. Methods Mol Biol (2009) 545, p233-242.
  3. Tanaka, K, and Hirota, T. Chromosome segregation machinery and cancer. Cancer Sci (2009) 100, p1158-1165.
  4. Tanaka, K, and Tanaka, T, U. Live cell imaging of kinetochore capture by microtubules in budding yeast. Methods Mol Biol (2009) 545, p233-242.
  5. Tanaka, T, U, Stark, M, J, and, Tanaka, K. Kinetochore capture and bi-orientation on the mitotic spindle. Nat Rev Mol Cell Biol (2005) 6, p929-942.
  6. Tanaka, K, and Tanaka, T, U. Molecular mechanisms of kinetochore capture by spindle microtubules. Experimental Medicine (2007) 25, p671-678.
  7. Tanaka, K, and Tanaka, T, U. Molecular mechanisms of kinetochore-microtubule interaction. Protein, Nucleic Acid and Enzyme (2006) 51, p1-9.

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  • Organizations and Research
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