Keiko Kawauchi

Mechanobiology Institute Alumni

MBI Senior Research Fellow 2010 – 2014

portrait-keikoKawauchiDr Keiko Kawauchi
Senior Assistant Professor
Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Japan 7-1-20, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan

email: kawauchi@center.konan-u.ac.jp
web: www.pi.konan-u.ac.jp/kawauchi

Keiko received her B.Sc. in Life Science from the Himeji Institute of Technology, Faculty of Science, Japan (1991 – 1995). After graduation, she worked as a researcher in the Ako Kasei Company Ltd., Japan (1995 – 1998) before pursuing a Ph.D. at the Himeji Institute of Technology, Graduate School of Science, Japan (1998 – 2002). She then worked at the Institute of Gerontology, Nippon Medical School, Japan, initially as a Postdoctoral Fellow (2003 – 2006), then as Assistant Professor (2006 – 2008) and Senior Assistant Professor (2008 – 2011). Concurrently, Keiko joined the Department of Biological Science, National University of Singapore, as a research fellow (2009 – 2010). Driven by her interest in the relationship between mechanotransduction and tumour progression, she joined the Mechanobiology Institute, Singapore (MBI) as Senior Research Fellow in 2010.

For more than 16 years, Keiko has dedicated herself to understanding biochemcial signalling pathways in cancer, as well as in the immune response. In particular, she has focused on studying the role of p53 in tumour suppression. After joining the MBI, her work was further focused towards understanding the relationship between p53 and the cytoskeletal processes that drive cell invasion.

The importance of p53

The human body is able to protect itself against a myriad of potentially harmful cellular events such as DNA damage, oxidative stress, osmotic shock and deregulated oncogene expression. This protection is often carried out at a molecular level with various proteins regulating and maintaining the health of cells via distinct protein signalling pathways.  One protein in particular, tumour suppressor p53, plays a significant role. This protein is localized in the nucleus where it monitors the integrity of the cell’s DNA, and functions as a transcription factor that controls the cell cycle. During normal cell growth, p53 is maintained at low levels via a continual proteasomal degradation mediated by the E3 ligase Mdm2. When cellular damage or oncogenic stresses are sensed, p53 is stabilized and activated to stimulate signalling pathways that decide either to repair the cell or induce apoptosis.

p53 and HtrA2-Omi

p53 and NF-kB

p53 is mutated or inactivated in almost 50% of human cancers, including many breast, cervical, colorectal and pancreatic cancers. This means p53’s ability to suppress tumorigenesis is often comprised, allowing the tumours to progress and spread. Due to the crucial role p53 plays in tumour suppression, understanding p53-dependent signalling pathways is important in the development of new anti-cancer therapies.

Opening pathways

Keiko joined MBI in 2010 where the role of mechanotransduction in tumorigenesis was of particular interest. Open discussions with other researchers in MBI provided a new perspective in which Keiko would investigate the role of p53-mediated mechanical signalling pathways in cancer progression. Her work was further strengthened by collaborations with the Institute of Gerontology, Nippon Medical School, Japan, and the Department of Biological Sciences, National University of Singapore, Singapore, and after several years working in the MBI, she made a significant impact in the field of oncology.

Her work culminated in the publication of two major papers in 2014. In one study Keiko revealed a novel role for p53 in the NF-kB-dependent regulation of actin cytoskeleton dynamics and STAT3 activity (Guo et al., J. Cell. Physiol. 2014). Here, the absence of p53 was found to constitutively enhance NF-kB activity, which promotes lamellipodia formation via integrin αvβ3-mediated signalling. During lamellipodia formation, activation of Rac I and Arp2/3 increases the recruitment of integrins, thereby creating a positive feedback loop which encourages the association of integrins and upstream STAT3 kinases, promoting STAT3 phosphorylation at the lamellipodia. Stiff extracellular substrates were shown to increase both NF-kB and STAT3 phosphorylation, and it was proposed that this is likely to promote tumour progression.

In this case, p53 suppresses tumorigenesis by inhibiting the NF-kB activity. This interferes with the positive feedback loop which would otherwise allow mechanical signals to be transduced by integrins, to promote lamellipodia formation and STAT3 phosphorylation.

keikoLab2.v2.cropped

Dr Kawauchi [far left] at the MBI microscopy facility with two of her students.

While continuing her investigations on the role of p53-mediated signalling in tumour suppression, Keiko also discovered that the protein could suppress oncogenic Ras-driven invasion by regulating the activation of HtrA2/Omi, which modulates actin cytoskeleton dynamics (Yamauchi et al., J. Cell Biol. 2014). In this case, p53 accumulation in the cytoplasm followed Ras transformation, and induced the activation of HtrA2/Omi by promoting the translocation of p38 MAPK into the mitochondria. Concurrently, oncogenic Ras stimulates mitochondrial fission independently of p53 expression, resulting in the release of the HtrA2/Omi into the cytosol. Activated HtrA2/Omi subsequently induces F-actin disassembly, leading to the downregulation of p130Cas phosphorylation and impairment of lamellipodia formation. This ultimately suppresses cell invasion.

In these studies the presence of functional p53 proved to be imperative for suppressing tumour growth and metastasis. However, it was equally clear that the activity of p53 is dependent on the integrity of many downstream signalling pathways. Thus, the identification of these pathways and their effect on actin dynamics may reveal novel molecular targets for cancer therapies.

Looking Forward

Keiko left MBI in 2014 to continue investigating p53 as a target in cancer therapy. This work will be carried out at the Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Japan. There, Keiko will focus on the role of the microenvironment in cancer metastasis. By further elucidating the role of p53 in mechanotransduction, Keiko aims to identify new molecular targets for cancer therapy.

Publications from Keiko’s time at MBI

K. Kawauchi, S. J. Wolf. Understanding p53: new insights into tumor suppression. Expert Rev. Anticanc. Therapy 14 (2014) 1101-1103. [PMID: 25119697]

H. Machiyama, H. Hirata, L. K. Loh, M. M. Kanchi, H. Fujita, S. H. Tan, K. Kawauchi, Y. Sawada. Displacement of p130Cas from focal adhesions links actomyosin contraction to cell migration. J. Cell Sci. 127 (2014) 3440-3450. [PMID: 24928898]

S. Yamauchi, Y. Y. Hou, K. A. Guo, H. Hirata, W. Nakajima, A. K. Yap, C. H. Yu, I. Harada, K. W. Chaim, Y. Sawada, K. Kawauchi. p53-mediated activation of the mitochondrial protease HtrA2/Omi prevents cell invasion. J. Cell Biol. 204 (2014) 1191-1207. [PMID: 24662565]

K. A. Guo, Y. Y. Hou, H. Hirata, S. Yamauchi, A. K. Yap, K. W. Chaim, Y. Sawada, K. Kawauchi. Loss of p53 enhances NF-kB-dependent lamellipodia formation. J. Cell. Physiol. 229 (2014) 696-704. [PMID: 24647813]

S. Higuchi, T. Watanabe, K. Kawauchi, T. Ichimura, H. Fujita. Culturing of mouse and human cells on soft substrates promote the expression of stem cell markers. J. Biosci. Bioengin. 117 (2014) 749-755. [PMID: 24360205]

K. Araki, K. Kawauchi, H. Hirata, M. Yamamoto, Y. Taya. Cytoplasmic translocation of the retinoblastoma protein disrupts sarcomeric organization. eLife 2 (2013) e01228. [PMID: 24302570]

S. Yamauchi, K Kawauchi, Y. Sawada. Myosin II-dependent exclusion of CD45 from the site of Fcγ receptor activation during phagocytosis. FEBS Lett. 586 (2012) 3229-3235. [PMID: 22771477]

K. Kawauchi, W. W. Tan, K. Araki, F. B. Abu Bakar, M. Kim, H. Fujita, H. Hirata, Y. Sawada. p130Cas-dependent actin remodelling regulates myogenic differentiation. Biochem. J. 445 (2012) 323-332. [PMID: 22587391]

T. M. Watanabe, S. Higuchi, K. Kawauchi, Y. Tsukasaki, T. Ichimura, H. Fujita. Chromatin plasticity as a differentiation index during muscle differentiation of C2C12 myoblasts. Biochem. Biophys. Res. Commun. 418 (2012) 742-747. [PMID: 22306010]