Prof. Karni's lab is interested in how the process of alternative RNA splicing (a fundamental step of gene expression) is de-regulated in cancer and other diseases, and how the proteins that control this process (splicing factors) contribute to cancer development, tumor progression and the metastatic process. The Karni lab uses various in vitro and in vivo cellular and animal systems as well as new technologies such as RNA-seq to identify the role of splicing factors in human diseases. One effort in the lab is to understand how alternative splicing is involved in cancer drug resistance and to modulate alternative splicing in order to sensitize resistant tumors to anti-cancer drugs. An additional project in the lab is to develop new therapies for the genetic disease Duchenne muscular dystrophy (DMD) which causes muscle degeneration and eventually death in affected children. Other applications of the studies in the lab include, discovery of early diagnostic markers for tumor development and patient prognosis as well as identification of new targets for the development of anti-cancer therapies. Some of these applications have been commercialized by the technology transfer company of the Hebrew University, Yissum.
Splicing factor oncoprotein SRSF1 is a transcriptional target of the c-myc proto-oncogene, and can be phosphorylated by SRPK or CLK downstream to Akt. SRSF1 alters the splicing of BIM, BIN1, S6K1 and Mnk2 regulating the mTOR and MAPK pathways, increasing translation and inhibiting apoptosis.
Back to top Current Projects
Back to top Laboratory Members
- To study the mechanisms of SRSF1 oncogenic activity in cancer
- To characterize the oncogenic and biochemical properties of S6K1 splicing isoforms and their role in cancer and signaling
- To characterize the oncogenic and biochemical properties of MNK2 splicing isoforms and their role in cancer and signal transduction
- To study the role of hnRNP A2/B1 in brain cancer (glioblastoma), hepatocellular carcinoma and metastatic breast cancer
- To identify the splicing changes that occur during ovarian and pancreatic cancer progression and their contribution to the metastatic process
- To study the role of alternative splicing of the insulin receptor and other splicing changes in pancreatic beta cell survival and diabetes
- To develop new therapies for Duchene muscular dystrophy
Prof. Rotem Karni, Ph.D.
Dr. Zahava Kluger
Dr. Pushkar Malakar
.D. Student.D. Student
Former lab members
Michal Cohen-Eliev (M.Sc, 2012). Now works at Shaare Zedek Medical Center
Lital Chartarifsky (M.Sc, 2013). Now a Ph.D. sudent, Watson School, CSHL, NY.
Ariel Sebag-Shimoni (Ph.D. 2014)Now a researcher at Sheba Medical Center.
Avi Maimon (Ph.D. 2014). Now a postdoc in the Faculty of Dental Medicine, Hebrew University.
Ilana Loinger-Lebenthal (Postdoc 2010-2013). Now works at Bar Ilan University Bioinformatics unit.
Liat Hai-Katvan (M.Sc, 2015) Now at Haifa University.
Asaf Shilo (Ph.D, 2016). Now a postdoc at the NCI, USA.
Vered Ben-Hur (Ph.D, 2015). Now at Raziel Therapeutics.
Back to top Selected Publications
Karni, R., Elisa de-Stanchina, David Mu, Scott Lowe, Rahul Sinha and Adrian Krainer. (2007) The gene coding for the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol. 14(3):185-93.
Karni, R., Hippo, Y., Lowe, S.W. and Krainer, A. (2008) The splicing factor oncoprotein SF2/ASF activates mTORC1. Proc. Natl. Acad. Sci. USA, 105:15323-7.
Golan-Gerstl, R., Cohen, M., Shilo, A., Suk-Suh, S., Bakacs, A., Coppola, L. and Karni, R. (2011). Splicing factor hnRNP A2/B1 regulates tumor suppressor gene splicing and is an oncogenic driver in glioblastoma. Cancer Res. 71, 4464-72.
Eshar, S., Allemand, E., Sebag, A., Glaser, F., Muchardt, C., Mandel-Gutfreund, Y., Karni, R. and Dzikowski R. (2012). A novel Plasmodium falciparum SR protein is an alternative splicing factor required for the parasites' proliferation in human erythrocytes. Nucleic Acids Res. 40: 9903-16.
Cohen-Eliav, M., Golan-Gerstl, R., Siegfried, Z., Andersen, CL,. Thorsen, K., Ørntoft, T.F,. Mu, D. and Karni, R. (2013). The splicing factor SRSF6 is amplified and is an oncoprotein in lung and colon cancers. J Pathol. 229: 630-9.
Ben Hur, V., Denichenco, P., Maimon, A., Krainer, A., Davidson, B. and Karni, R. (2013). S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1. Cell Reports, 3: 103–115.
Shimoni-Sebag, A., Lebenthal-Loinger, I., Zender, L. and Karni, R. (2013). RRM1 domain of the splicing oncoprotein SRSF1 is required for MEK1-MAPK-ERK activation and cellular transformation. Carcinogenesis. 34: 2498-504.
Siegfried, Z., Bonomi, S., Ghigna, C. and Karni, R. (2013). Regulation of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing in cancer. Int J Cell Biol. (Review). 2013: ID 568931.
Maimon, A., Mogilevsky, M., Shilo, A., Golan-Gerstl, R., Obiedat, A., Ben Hur, V., Lebenthal-Loinger, I., Stein, I., Reich, R., Beenstock, J., Zehorai, E., Andersen, C.L., Thorsen, K., Ørntoft, T.F., Davis, R.J., Davidson, B., Mu, D. and Karni, R. (2014). Mnk2 alternative splicing modulates the p38-MAPK pathway and impacts Ras-induced transformation. Cell Reports. 7: 501-13.
Shilo, A., Ben Hur, V., Denichenko, P., Stein, I., Pikarsky, E., Rauch, J., Kolch, W., Zender, L. and Karni, R. (2013) Splicing Factor hnRNP A2/B1 activates the Ras-MAPK-ERK pathway controlling A-Raf splicing in hepatocellular carcinoma development. RNA. 20: 505-15.
Shilo, A., Siegfried, Z. and Karni, R. (2014). The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression. Molecular and Cellular Oncology. (Review). 1: e970955
Danan-Gotthold, M., Golan-Gerstl, R., Eisenberg, E., Meir, K., Karni, R. and Levanon, E.Y. (2015). Identification of recurrent regulated alternative splicing events across human solid tumors. Nucleic Acids Res. 43:5130-44.
Malakar P, Chartarifsky L, Hija A, Leibowitz G, Glaser B, Dor Y, Karni R. (2016). Insulin receptor alternative splicing is regulated by insulin signaling and modulates beta cell survival. Sci Rep. 6:31222.
Malakar P, Shilo A, Mogilevsky A, Stein I, Pikarsky E, Nevo Y, Benyamini H, Elgavish S, Zong X, Prasanth KV, Karni R. (2016). Long Noncoding RNA MALAT1 Promotes Hepatocellular Carcinoma Development by SRSF1 Upregulation and mTOR Activation. Cancer Res. doi: 10.1158/0008-5472
Back to top Patents
Back to top
- Rotem Karni. Splicing Factor Activity for Detecting and Treating Cancer (2015), Yissum, (Approved in the US).
- Avraham Maimon, Vered Ben Hur, Rotem Karni. Methods of Treating and Diagnosing Diseases Using Agents that Regulate the Alternative Splicing Pathway (2012). Yissum, PCT applied in the US.
- Regina Golan-Gerstl, Rotem Karni. Decoy oligonucleotides for the treatment of diseases. (2016), Yissum, PCT submitted in the US.