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Kazuko Nishikura, Ph.D.

Kazuko Nishikura, Ph.D.

  • Professor, Gene Expression and Regulation Program
  • 215-898-3828, Office
  • 215-898-3907, Lab
Summary

The Kazuko Nishikura laboratory is exploring the phenomenon of RNA editing, a process by which a single gene can produce a number of closely related but distinct proteins as well as non-coding RNAs such as microRNAs. RNA carries the genetic instructions of DNA to the cellular machinery responsible for synthesizing the proteins of the body. In addition, non-coding RNAs play important roles in gene regulation without being translated into proteins. As Nishikura and her colleagues are discovering, however, RNA editing has a much more complex role in regulating gene expression. Recent studies also suggest that disruptions in RNA editing may play a role in regulation of metabolism and depression.

Dr. Nishikura first joined The Wistar Institute in 1982, and became a full professor in 1995. Raised in the Ishikawa Prefecture along the western coast of Japan, Dr. Nishikura went to Kanazawa University, where she received both a bachelor’s and master’s degree in biochemistry. Dr. Nishikura obtained her Ph.D. in medical science from Osaka University, but much of her thesis work (on the properties by which oxygen binds to hemoglobin in red blood cells) was performed in the laboratory of Dr. Max F. Perutz at the Medical Research Council Laboratory of Molecular Biology (LMB) in Cambridge, England.  She returned to the LMB for her first postdoctoral fellowship working in laboratories of Dr. Eddy De Robertis and Sir John B Gurdon, before obtaining a second fellowship at Stanford University, where she explored the role of RNA processing in the immunoglobulin heavy chain gene expression in the laboratory of Dr. Roger D. Kornberg.

Dr. Nishikura continued her work on RNA biochemistry and molecular biology at Wistar, where her laboratory has made pioneering strides in the understanding of how our cells utilize RNA to control gene expression and protein synthesis. Among their chief accomplishments was the discovery and characterization of a family of enzymes called ADAR (adenosine deaminases acting on RNA), which can affect how proteins are made by editing the RNA transcribed from DNA. This alteration allows a single gene to create multiple proteins, and the Nishikura laboratory has worked to understand how the malfunction of this process can lead to disease, including some psychiatric disorders and metabolic diseases.

The research team has also investigated the interaction of ADAR proteins with other cellular proteins. In particular, the laboratory is interested in the tendency of ADAR to form large multipart protein complexes, and the exact role these complexes play in the biology of the cell.  Most recently, they discovered that ADAR1 forms a complex with Dicer to play a major role in the control of RNA interference mechanism.

Selected Publications

1.   Nishikura, K., Sakurai, M., Ariyoshi, K., and Ota, H.  2013.  Antagonistic and stimulative roles of ADAR1 in RNA silencing: an editor's point-of-view.  RNA Biol. 19: 1240-1247. PMID: 23949595

2.   Morita, Y., Shibutani, T., Nakanishi, N., Nishikura, K., Iwai, S., and Kuraoka, I. 2013.  hEndV is a ribonuclease specific for inosine-containing dsRNA.  Nat. Commun. 4: 1-10 (doi:10.1038/ncomms3273). PMID: 23912718

3.   Ota, H., Sakurai, M., Gupta, R., Valente, L., Wulff, B-E, Ariyoshi, K., Iizasa, H., Davuluri, R.V., and Nishikura, K. 2013.  ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing. Cell 153: 575-589. PMCID: PMC3651894.

4.    Tsuruoka, N., Arima, M., Yoshida, N., Okada, S., Sakamoto, A., Hatano, M., Satake, H., Arguni, E., Wang, J., Yang, J., Nishikura, K., Sekiya, S., Shozu, M., and Tokuhisa, T.  2013. ADAR1 protein induces adenosine-targeted DNA mutations in senescent Bcl6-deficient cells. J. Biol. Chem. 288: 826-836. PMCID: PMC3543032.

5.   Wulff, B-E and Nishikura, K. 2012. Modulation of microRNA expression and function by ADARs. Curr. Top. Microbiol. Immunol. 353: 91-109.  PMID: 21761289.

6.   Wulff BE, Sakurai M, Nishikura K., Elucidating the inosinome: global approaches to adenosine-to-inosine RNA editing., Nature Reviews Genetics. 2011;12:81-5. 21173775

7.    Iizasa H, Wulff BE, Alla NR, Maragkakis M, Megraw M, Hatzigeorgiou A, Iwakiri D, Takada K, Wiedmer A, Showe L, Lieberman P, Nishikura K., Editing of Epstein-Barr-virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency., Journal of Biological Chemistry. 2010;285:33358-70. 20716523

8.     Nishikura K., Functions and regulation of RNA editing by ADAR deaminases., Annual Review of Biochemistry. 2010;79:321-49. 20192758

9.     Iizasa H, Nishikura K., A new function for the RNA-editing ADAR1., Nature Immunology. 2009;10:16-8. Comment on: Nat Immunol. 2009;10:109-15. 19088736

10.    Kawahara Y, Grimberg A, Teegarden S, Mombereau C, Liu S, Bale TL, Blendy JA, Nishikura K., Dysregulated editing of serotonin 2C receptor mRNAs results in energy dissipation and loss of fat mass., Journal of Neuroscience. 2008;28:12834-44. 19036977

11.    Kawahara Y, Megraw M, Kreider E, Iizasa H, Valente L, Hatzigeorgiou AG, Nishikura K., Frequency and fate of microRNA editing in human brain., Nucleic Acids Research. 2008;36:5270-80. 18684997

12.    Kawahara Y., Zinshteyn, B., Sethupathy, P., Iizasa, H., Hatzigeorgiou, A.G., and Nishikura, K. Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science. 2007;315:1137-1140. 17322061

13.    Kawahara Y., Zinshteyn, B., Chendrimada, T.P., Shiekhattar, R., and Nishikura, K. RNA editing of microRNA-151 blocks cleavage by the Dicer-TRBP complex. EMBO Reports. 2007;8:763-769. 17599088

14.    Nishikura K. 2006. Editor meets silencer: crosstalk between RNA editing and RNA interference. Nat Rev Mol Cell Biol 7: 919-931. PMID: 17139332

15.     Wang Q, Khillan J, Gadue P and Nishikura K. 2000. Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science 290: 1765-1768. PMID: 11099415