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  • Prof.  Rotem Karni

Research Interests
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.
Current Projects
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 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 Duchenne muscular dystrophy. 

Laboratory Members
Prof. Rotem Karni,Ph.D.
Principal Investigator
Dr. Zahava Kluger
Lab Manager
Dr. Regina Golan-Gerstl
Research associate
Dr. Vered Ben-Hur
Research associate
Dr. Pushkar Malakar
Postdoctoral Fellow
Polina Denichenko
Ph.D. Student
 Asaf Shilo
Ph.D. Student
Maxim Mogilevsky
Ph.D. Student
Dr. Jasmine Cohen (MD)
Ph.D. student
Adi Rosenberg
M.Sc. Student
Amina Jbara
M.Sc. student
Alona Peretz
Undergrad student
Adi Amar
Undergrad 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 postdoc at Hadassah 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).
Karni, R., Jove, R. and Levitzki, A. (1999) Inhibition of pp60c-Src reduces Bcl-XL levels and reverses the transformed phenotype of cells overexpressing EGF and HER-2 receptors. Oncogene 18:4654-4662.
Karni, R. and Levitzki, A. (2000) c-Src is a caspase-3 substrate and is essential for the transformed phenotype of A431 cells. Mol. Cell. Biol. Res. Com. 3, 98-104.
Karni, R., Dor, Y., Meyuhas, O., Keshet, E. and Levitzki, A. (2002) Activated pp60c-Src leads to elevated HIF-1α expression under normoxia. J. Biol. Chem. 277(45):42919-42925.
Karni, R., Mizrachi, S., Gazit, A., Reiss-Sklan, E., Livnah, O. and Levitzki, A. (2003) The pp60c-Src inhibitor PP1 is non-competitive against ATP. FEBS Lett. 537(1-3):47-52.
Karni, R., Gus, Y., Dor, Y., Meyuhas, O. and Levitzki, A. (2005) Active Src Elevates the Expression of ß-catenin by Enhancement of Cap-dependent Translation. Mol. Cell Biol. 12:5031-9.
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.
 b. highlighted in Nature Reviews Cancer
Gus, Y., Karni, R. and Levitzki. A. (2007) Subunit S5a of the 26S proteasome is regulated by antiapoptotic signals. FEBS J. 274:2815-31.
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.
Sun, S., Zhang, Z., Sinha, R., Karni, R. and Krainer A. (2010) SF2/ASF Autoregulation involves multiple mechanisms. Nat Struct Mol Biol. 17: 306-12.
Sinha, R., Allemand, E., Zhang, Z., Karni, R., Myers, M.P. and Krainer, A. (2010) Arginine methylation controls the subcellular localization and functions of the oncoprotein splicin. factor SF2/ASF. Mol Cell Biol. 30: 2762-74.
Thorsen, K., Mansilla, F., Schepeler, T., Øster, B., Rasmussen, M.H., Dyrskjøt, L., Karni, R, Akerman, M., Krainer, A., Laurberg, S., Andersen, C.L. and Ørntoft, T.F. (2010) Alternative splicing of SLC39A14 in colorectal cancer is regulated by the Wnt pathway. Mol Cell Proteomics. 2011 10:M110.002998
Shay Porat, Noa Weinberg-Corem, Sharona Tornovsky-Babaey, Rachel Schyr-Ben-Haroush, Ayat Hija, Miri Stolovich-Rain, Daniela Dadon, Zvi Granot, Vered Ben-Hur, Peter White, Christophe A. Girard, Rotem Karni, Klaus H. Kaestner, Frances M . Ashcroft, Mark A. Magnuson, Ann Saada, Joseph Grimsby, Benjamin Glaser and Yuval Dor (2011) Control of Pancreatic β Cell Regeneration by Glucose Metabolism. Cell Metab. 13: 440-9.
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.
Anczuków, O., Rosenberg, A.Z., Akerman, M., Das, S., Zhan, L., Karni, R., Muthuswamy, S.K. and Krainer, A.R. (2012). The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nat Struct Mol Biol. 19: 220-8.
Sebban, S., Golan-Gerstl, R., Karni, R., Vaksman, O., Davidson, B. and Reich, R. (2012). Alternatively spliced lysyl oxidase-like 4 isoforms have a pro-metastatic role in cancer. Clin Exp Metastasis. 30: 103-17.
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.
Li, D., Yang, H., Nan, H., Liu, P., Pang, S., Zhao, Q., Karni, R., Kamps, M.P., Xu, Y., Zhou, J., Wiedmer, T., Sims, P.J. and Wang, F. (2012). Identification of key regulatory pathways of myeloid differentiation using an mESC-based karyotypically normal cell model. Blood. 120: 4712-9.
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.
Hochberg, M., Gilead, L., Safran, M., Markel, G., Nemlich, Y., Enk, D., Denichenko, P., Karni, R. and Ingber, A. (2013). Insulin-like Growth Factor Binding Protein-7 (IGFBP7) transcript: A-to-I editing events in normal and cancerous human keratinocytes. Arch Dermatol Res. 305: 519-28.
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. (2015). The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression. Mol. Cell. Oncology. (Review, in press).
Danan-Gotthold, M., Golan-Gerstl, R., Eisenberg, E., Meir K., Karni, R*. and Levanon, E*. (2015)., Identification of recurrent regulated alternative splicing events across human solid tumors. Nucleic Acids Res. (in press).

PatentsRotem Karni. Splicing Factor Activity for Detecting and Treating Cancer (2009), Yissum, (Registered in the US/EU).
Avraham Maimon, Rotem Karni. Diagnosis and treatment of cancer by detection of, or manipulation of the expression of MKNK2 splicing isoforms. (2012). Provisional submitted in the US/EU
Vered Ben Hur, Rotem Karni. S6K as diagnostic marker for cancer, as a target for anti cancer therapy and as an indicator for response to anti-cancer drugs. (2012). Provisional submitted in the US/EU
Rotem Karni. Use of the levels of splicing factor SRSF6 for diagnosis and prognosis and its inhibition for treatment of cancer and Inflammatory bowel disease (IBD). (2012). Provisional submitted in the US/EU
Regina Golan-Gerstl, Rotem Karni. Decoy oligonucleotides for the treatment of diseases. (2014), Yissum, provisional patent submitted in the US/EU.
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