Contact

Nara Institute of Science and Technology,Graduate School of Biological Sciences
Tumor Cell Biology Laboratory KATO LAB

8916-5 Takayama, Ikoma, Nara 630-0101, Japan
Phone: +81-743-72-5512
Fax: +81-743-72-5519

Key Words

Cell Cycle, G1 Progression, Cyclin, Cdk Inhibitor, Tumorigenesis, Hematopoiesis, Regenerative Medicine, Cancer Research

Staff

Jun-ya Kato Professor jkata@bs.naist.jp
Noriko Kato Assistant Professor noriko-k@bs.naist.jp

Overvie

The proliferation of mammalian cells is strictly regulated by extracellular signals, which primarily act during the first gap (G1) phase of the cell cycle. Progression through G1 and subsequent transition into S phase are both positively and negatively regulated by G1 regulators. Among this series of factors, the D-type G1 cyclins and the Cdk inhibitor, p27Kip1, are the cellular targets of growth factors, which integrate extracellular signals to the core cell cycle regulators. Alterations in G1 regulator genes are often found in human tumors, indicating that G1 regulators participate in both tumor suppression and cell proliferation. To elucidate the molecular mechanisms governing cell proliferation and tumorigenesis, our research focuses on identifying the physiological functions of critical G1 regulators. We have utilized a variety of genetic, biological, and biochemical approaches to address this question.

(1) Mammalian tissue culture system:

Using a variety of cell lines and culture conditions, we analyze cell cycle progression, cellular differentiation, cellular senescence and apoptosis in vitro. By modulating both the expression levels and activities of particular factors through the transfection of expression vectors, expression of siRNA or introduction of inhibitory antibodies, we have examined their cellular functions. To avoid effects resulting from the genetic mutations in immortalized cell lines, we have also utilized the primary cell culture system.

(2) Human genetics:

We have investigated the genetic alterations associated with human diseases to examine the role of G1 regulators in tumorigenesis. We are particularly interested in searching for mutations, deletions, aberrant expression patterns and gene translocations that are associated with hematopoietic malignancies, expecting to reveal the regulatory mechanism of blood cell proliferation, differentiation and survival.

(3) Reverse genetics:

We will evaluate the physiological significance of findings obtained above by artificially altering the genetic structure of molecules of interest in mice and examine the subsequent effect of these modifications in the experimental animal model. This approach includes the manipulation of ES cells, which are induced to differentiate into multiple cell lineages in vitro.

Research Areas

1. Molecular mechanism of G1 progression in mammalian cells. 
- Identification and functional analysis of the upstream regulators of the Cdk inhibitor, p27Kip1.

2. Genetic analysis of human tumor cells. 
- Identification of genetic abnormalities in cell cycle regulator genes.

3. Molecular mechanism of hematopoiesis. 
- Identification of genes whose products influence hematopoiesis. 
- Analysis of their involvement in human hematopoietic malignancies.

4. Molecular function of the mammalian COP9 signalosome complex

References

1. Kato JY, Sherr CJ. (1993) Inhibition of granulocyte differentiation by G1 cyclins D2 and D3 but not D1. Proc Natl Acad Sci U S A, 90, 11513-7.

2. Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ. (1993) Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev, 7, 331-42.

3. Quelle DE, Ashmun RA, Shurtleff SA, Kato JY, Bar-Sagi D, Roussel MF, Sherr CJ. (1993) Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev, 7, 1559-71.

4. Kato JY, Matsuoka M, Polyak K, Massague J, Sherr CJ. (1994) Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Cell, 79, 487-96.

5. Kato JY, Matsuoka M, Strom DK, Sherr CJ. (1994) Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase. Mol Cell Biol, 14, 2713-21.

6. Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ, Kato JY. (1994) D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol, 14, 2066-76.

7. Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A. (1994) p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev, 8, 9-22.

8. Kitagawa M, Higashi H, Jung HK, Suzuki-Takahashi I, Ikeda M, Tamai K, Kato J, Segawa K, Yoshida E, Nishimura S, Taya Y. (1996) The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. Embo J, 15, 7060-9.

9. Kurokawa K, Tanaka T, Kato J. (1999) p19ARF prevents G1 cyclin-dependent kinase activation by interacting with MDM2 and activating p53 in mouse fibroblasts. Oncogene, 18, 2718-27.

10. Tomoda K, Kubota Y, Kato J. (1999) Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature, 398, 160-5.

11. Yoneda-Kato N, Fukuhara S, Kato J. (1999) Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein. Oncogene, 18, 3716-24.

12. Shen L, Tsuchida R, Miyauchi J, Saeki M, Honna T, Tsunematsu Y, Kato J, Mizutani S. (2000) Differentiation-associated expression and intracellular localization of cyclin-dependent kinase inhibitor p27KIP1 and c-Jun co-activator JAB1 in neuroblastoma. Int J Oncol, 17, 749-54.

13. Sugiyama Y, Tomoda K, Tanaka T, Arata Y, Yoneda-Kato N, Kato J. (2001) Direct binding of the signal-transducing adaptor Grb2 facilitates down-regulation of the cyclin-dependent kinase inhibitor p27Kip1. J Biol Chem, 276, 12084-90.

14. Tomoda K, Kubota Y, Arata Y, Mori S, Maeda M, Tanaka T, Yoshida M, Yoneda-Kato N, Kato JY. (2002) The cytoplasmic shuttling and subsequent degradation of p27Kip1 mediated by Jab1/CSN5 and the COP9 signalosome complex. J Biol Chem, 277, 2302-10.

15. Tsuchida R, Miyauchi J, Shen L, Takagi M, Tsunematsu Y, Saeki M, Honna T, Yamada S, Teraoka H, Kato JY, Mizutani S. (2002) Expression of Cyclin-dependent Kinase Inhibitor p27/Kip1 and AP-1 Coactivator p38/Jab1 Correlates with Differentiation of Embryonal Rhabdomyosarcoma. Jpn J Cancer Res, 93, 1000-6.

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