Nara Institute of Science and Technology
Graduate School of Science and Technology 
Division of Biological Science
Laboratory of Tumor Cell Biology (KATO LAB)

8916-5 Takayama, Ikoma, Nara 630-0101, Japan
Phone: +81-743-72-5510
Fax: +81-743-72-5519

Key Words

Cell Cycle, G1 Progression, Tumorigenesis, Hematopoiesis, Leukemogenesis, Cancer Research, Cancer Metabolism, ROS Regulation


Jun-ya Kato 
Noriko Kato 
Takashi Yokoyama
Ikuko Nakamae


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

5.   Cancer metabolism
- Regulation of ROS
- Anti-oxidant system in cancer (GSH and TXN)
- Curcumin (anti-tumorigeniuc activity)
- Curcumin analogs


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. Yoneda-Kato, N., Tomoda, K., Umehara, M., Arata, Y., and Kato, J. Y.. Myeloid leukemia factor 1 regulates p53 by suppressing COP1 via COP9 signalosome subunit 3. EMBO J. 24: 1739-1749, 2005.

13. Yoneda-Kato, N., Kato, J.Y. Shuttling imbalance of MLF1 results in p53 instability and increases susceptibility to oncogenic transformation. Mol Cell Biol. 28: 422-434, 2008.

14. Kato JY, and Yoneda-Kato N. Mammalian COP9 signalosome. (Review) Genes to Cells 14: 1209-25, 2009.

15. CSN5 specifically interacts with CDK2 and controls senescence in a cytoplasmic cyclin E-mediated manner.
Yoshida A, Yoneda-Kato N, Kato JY.
Sci Rep. 2013;3:1054. doi: 10.1038/srep01054. Epub 2013 Jan 11.

16. COP1 targets C/EBPα for degradation and induces acute myeloid leukemia via Trib1.
Yoshida A, Kato JY, Nakamae I, Yoneda-Kato N.
Blood. 2013 Sep 5;122(10):1750-60. doi: 10.1182/blood-2012-12-476101. Epub 2013 Jul 24.

17. Myeloid leukemia factor 1 stabilizes tumor suppressor C/EBPα to prevent Trib1-driven acute myeloid leukemia.
Nakamae I, Kato JY, Yokoyama T, Ito H, Yoneda-Kato N.
Blood Adv. 2017 Sep 1;1(20):1682-1693. doi: 10.1182/bloodadvances.2017007054. eCollection 2017 Sep 12.

18. Larasati YA, Yoneda-Kato N, Nakamae I, Yokoyama T, Meiyanto E, Kato JY. Curcumin targets multiple enzymes involved in the ROS metabolic pathway to suppress tumor cell growth. Sci Rep. 2018 Feb 1;8(1):2039. doi: 10.1038/s41598-018-20179-6.