Prof. Nir Uri
List of Publications
Chapters in Reviewed Books
1. Nir, U. (1976). Studies on the interaction between valinomycin and reticulocyte membranes and its effects on protein synthesis. M.Sc. Thesis, Bar-Ilan University:
2. Nir, U., Walker, M.D. & Rutter, W.J. (1987). Negative regulation of rat insulin 1 gene expression. In: Transcriptional Control Mechanisms (D.K. Granner, R. Rosenfield & S. Chang, Eds.), UCLA Symp. Mol. Cell. Biol., New Series Vol. 52, Alan R. Liss, N.Y., pp. 123-133.
3. Walker, M.D., Karlsson, O., Edlund, T., Barnett, J., Nir, U. & Rutter, W.J. (1987). Cell specific expression of the rat insulin gene. In: Molecular Approaches to Developmental Biology (R.A. Firtel & E.H. Davidson, Eds.), UCLA Symp. Mol. Biol. New Series Vol. 5, Alan R. Liss, N.Y., pp. 619-627.
4. Walker, M.D., Karlsson, O., Edlund, T., Barnett, J., Nir, U. Rutter, W.J. (1987). Identification of DNA sequences involved in expression of the rat insulin gene. In: Molecular Mechanisms in the Regulation of Cell Behavior (C. Waymouth, ed.), Alan R., Liss, N.Y., pp. 273-278.
5. Nir, U., Moss, L.G., Fodor, E., Meister, A., Weinrich, S., Melloul, D. & Rutter, W.J. (1987). Analysis of cellular factors binding to cis-acting regulatory elements of pancreatic genes. In: Mechanisms of Control of Gene Expression. UCLA Symp. Mol. Cell. Biol. New Series Vol. 67 (B. Cullen, L.P. Gage, M.A.W. Siddiqui, A.M. Skalka & H. Weissbach, eds), Alan R. Liss, N.Y., pp. 135-145.
6. Walker, M.D., Karlsson, O., Edlund, T., Nir, U., Barnett, J. Rutter, W.J. (1988). Regulation of rat insulin 1 gene expression. In: Selected Topics in Molecular Endocrinology (Y.F.C. Lau, ed.), Oxford University Press, pp. 59-74.
Articles in Reviewed Journals
7. Herzberg, M. & Nir, U. (1980). Interaction between membranal properties and protein synthesis in reticulocytes: Influence of trypsinization on H3‑valinomycin action. Mol. Biol. Rep. 6: 131-141
8. Weissenbach, J., Chernajovsky, Y., Zeevi, M., Shulman, L., Soreq, H., Nir, U., Wallach, D., Perricaudet, M., Tiollaus, P. & Revel, M. (1980). Two interferon mRNAs in human fibroblasts: in vitro translation and E. coli cloning studies. Proc. Nat. Acad. Sci. USA 77: 7152-7156.
9. Mory, Y., Chernajovsky, Y., Feinstein, S., Chen, L., Nir, U., Weissenbach, J., Malpiece, Y., Tiollais, P., Marks, D., Lodner, M., Colby, C. & Revel, M. (1981) Synthesis of human interferon 1b in E. coli infected by a lambda phage recombinant containing a human genomic fragment. Eur. J. Biochem. 120: 197‑202.
10. Fellous, M., Nir, U., Wallach, D., Merlin, G., Rubinstein, M. & Revel, M. (1982). Interferon dependent induction of mRNA for the major histocompatibility antigens in human fibroblasts and lymphoblastoid cells. Proc. Nat. Acad. Sci. USA 79: 3082-3086.
11. Nir, U., Cohen, B., Chen, L & Revel, M. (1984). A human IFN-1b gene deleted of promoter sequences upstream from the TATA box is controlled post‑transcriptionally by ds RNA. Nucl. Acids Res. 12: 6979-6993.
12. Feinstein, S.I., Mory, Y., Chernajovsky, Y., Maroteaux, L., Nir, U., Lavie, V. & Revel, M. (1985). Family of human _a-interferon-like sequences. Mol. Cell. Biol. 5: 422-430.
13. Nir, U., Maroteaux, L., Cohen, B. & Mory, Y. (1985). Priming affects the transcription rate of human interferon 1b gene. J. Biol. Chem. 260: 14242-14247.
14. Nir, U., Walker, M.D. & Rutter, W.J. (1986). Regulation of rat insulin 1 gene expression: Evidence for negative regulation in non-pancreatic cells. Proc. Nat. Acad. Sci. U.S.A. 83: 3180-3184.
15. Nir, U., Fodor, E. & Rutter, W.J. (1988). Capturing Nuclear Sequence Specific DNA Binding Proteins Using SV40 Derived Minichromosomes. Mol. Cell. Biol. 8(2): 982-987.
16. Nir, U., Fodor, E., & Rutter, W.J. (1989). Detection of Enhancer Binding Proteins Using SV40 Derived Minichromosomes. DNA and Protein Engineering Techniques. 1(5): 61-65.
17. Fischman, K., Edman, J., Shackelford, G.M., Turner, J.A., Rutter, W.J. & Nir, U. (1990). A murine FER testis specific transcript (fer T) encodes A truncated FER protein. Mol. Cell. Biol. 10(1): 146-153.
18. Keshet, E., Itin, A., Fischman, K. & Nir, U. (1990). The testis-specific transcript (fer T) of the tyrosine kinase FER is expressed during spermatogenesis in a stage specific manner. Mol. Cell. Biol. 10(9): 5021-5025.
19. Nir, U., Ladan, H., Malik, Z. & Nitzan, Y. (1991) In vivo effects of porphyrins on Bacterial DNA.
J. Photochem & Photobiol. 11: 295-306.
20. Hazan, B., Bern, O., Carmel, M., Lejbkowicz, F., Goldstein, R.S. & Nir, U. (1993) Fer T encodes a
51 kDa meiosis specific nuclear tyrosine kinase. Cell Growth & Differentiation 4: 443-449.
21. Navon, A., Schwartz, Y., Hazan, B., Kassir, Y. & Nir, U. (1994) Meiosis dependent tyrosine phosphorylation of a yeast protein related to the mouse p51ferT. Mol. Gen. Genet. 244: 160-167.
22. Mittelman, M., Gardyn, J., Carmel, M., Malovani, H., Barak, Y. & Nir, U. (1995) Analysis of the Erythropoietin receptor gene in patients with myeloproliferative and myelodysplastic syndromes. Leukemia Research 20: 459-466.
23. Yaffe, A., Schwartz, Y., Hacohen, D., Kinar, Y., Nir, U. & Salzberg, S. (1996) Inhibition of 2’-5’A synthetase expression by antisense RNA interferes with interferon mediated antiviral and antiproliferative effect and induces anchorage independent cell growth. Cell Growth & Differentiation 7: 969-978.
24. Bern, O., Hazan, B. & Nir, U. (1997) Growth-dependent subnuclear localization of a 66 kDa phosphoprotein in FER protein overexpressing cells. FEBS Lett. 403: 45-50.
25. Halachmy, S., Bern, O., Schreiber, L., Carmel, M., Sharabi, Y., Shoham, J. & Nir, U. (1997) p94fer facilitates cellular recovery of gamma irradiated pre-T cells. Oncogene 14: 2871-2880.
26. Theodor, L., Shoham, J., Berger, R., Gokkel, E., Trachtenbrot, L., Simon, A.J., Brok-Simon, F.,
Nir, U., Ilan, E., Zevin-Sonkin, D., Friedman, E. and Rechavi, G. (1997) Ubiquitous expression of a cloned murine thymopoietin RNA. Acta Haematol. 97: 153-163.
27. Salzberg, S., Hyman, T., Turm, H., Kinar, Y., Schwartz, Y., Nir, U., Lejbkowicz, F. and
Huberman, E. (1997) Ectopic expression of 2-5A synthetase in human myeloid leukemia cells induces cell-growth arrest and facilitates the appearance of a myeloid differentiation marker. Cancer Res. 57: 2732-2740.
28. Schwartz, Y., Ben-Dor, I., Motro, B. and Nir, U. (1998) Tyrosine phosphorylation of the TATA Modulatory Factor (TMF) by the FER nuclear tyrosine kinases. FEBS Lett. 434: 339-345.
29. Ben-Dor, I., Bern, O., Tennenbaum, T. and Nir, U. (1999) The cell-cycle dependant nuclear accumulation of the p94fer tyrosine-kinase is regulated by its N-terminus and is affected by kinase-domain integrity and ATP binding. Cell Growth & Differentiation 10:113-129.
30. Sharabani-Yosef, O., Bak, A., Langzam, L., Lui, Z., Nir, U., Braiman, L., Sweadner, K.J. and Sampson, S.R. (1999) Rat skeletal muscle in culture expresses the a1 but not the a2 protein subunit isoform of the Na+/K+ pump. J. Cell. Physiol. 180: 236-244.
31. Carmel, M., Shpungin, S. and Nir, U. (2000) Role of positive and negative regulation in modulation of the Fer promoter activity. Gene 241: 87-99.
32. Orlovsky K., Ben-Dor, I., Priel-Halachmi, S., Malovany, H. and Nir, U. (2000) N-terminal sequences direct the autophosphorylation states of the FER tyrosine kinases in vivo. Biochemistry 39: 11084-11091.
33. Priel-Halachmi, S., Ben-Dor, I., Shpungin, S., Tennenbaum, T., Malovani, H., Bachrach, M., Salzberg, S. and Nir, U. (2000) FER kinase activation of Stat3 is determined by the N-terminal sequence. J. Biol. Chem. 275: 28902-28910.
34. Sharabani-Yosef, O., Bak, A., Nir, U. and Sampson, S.R. (2001). Na+/K+ pump expression in the L8 rat myogenic cell line: Effects of heterologous alpha subunit transfection. J. Cell. Physiol. 187:
35. Beery, R., Haimsohn, M., Wertheim, N., Hemi, R., Nir, U., Karasik, A., Kanety, H. and Geier, A. (2001) Activation of the insulin-like growth factor 1 signaling pathway by the antiapoptotic agents aurintricarboxylic acid and evans blue. Endocrinology 142: 3098-3107.
36. Dagon, Y., Dovrat, S., Vilchik, S., Hacohen, D., Shlomo, G., Sredni, B., Salzberg, S. and Nir, U. (2001) Double-stranded RNA-dependent protein kinase, PKR, down-regulates CDC2/cyclin B1 and induces apoptosis in non-transformed but not in v-mos transformed cells. Oncogene 20: 8045-8056.
37. Orlovsky, K., Theodor, L., Malovani, H., Chovers, Y., and Nir, U. (2002) Gamma Interferon Down-Regulates Fer and Induces its Association with Inactive Stat3 in Colon Carcinoma Cells. Oncogene 21: 4997-5001.
38. Sharabani-Yosef, O., Nir, U. and Sampson, S.R. (2002) Thyroid hormone up-regulates Na+/K+ pump a2 mRNA but not a2 protein isoform in cultured skeletal muscle. Biochim. Biophys. Acta 1573:
39. Taler, M., Shpungin, S., Salem, Y., Malovani, H., Pasder, O. and Nir, U. (2003) Fer is a downstream effector of insulin and mediates the activation of Stat3 in myogenic cells. Mol. Endocrinol. 17:
40. Perry, E., Tsruya, R., Levitzky, P., Pomp, O., Taler, M., Weisberg, S., Parris, W., Kulkarni, S., Malovani, H., Pawson, T., Shpungin, S. and Nir, U. (2004) TMF/ARA160 is a “BC box” containing protein that mediates the degradation of Stat3. Oncogene 23: 8908-8919.
41. Salem, Y., Shpungin, S., Pasder, O., Pomp, O., Taler, M., Malovani, H. and Nir, U. (2005) Fer kinase sustains the activation of ERK1/2 and the production of VEGF in hypoxic cells. Cell. Signaling 17(3): 341-353.
42. Pasder, O., Shpungin, S., Vilchick, S., Michaeli, S., Salem, Y., Malovani, H. and Nir, U. (2006) Down-regulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells. Oncogene 25: 4194-4206.
43. Volpe, M., Shpungin, S., Barbi, C., Abraham, G., Malovani, H., Wides, R. and Nir, U. (2006) trnp: A conserved mammalian gene encoding a nuclear protein that accelerates cell-cycle progression. DNA & Cell Biol. 25: 331-339 (with cover).
44. Hayun, R., Shpungin, S., Malovani, H., Albeck, M., Okun, E., Nir*, U. and Sredni*, B. (2007) Novel involvement of the immunomodulator AS101 in IL-10 signaling, via the tyrosine kinase Fer. Ann NY Acad Sci. 1095:240-250 (* Equal contribution).
45. Pasder, P., Salem, Y., Yaffe, E., Shpungin, S. and Nir, U. (2007) Fer as a novel target for cancer therapy. Drugs of the Future 32: 61-70 (Review).
46. Abu, A., Frydman, M., Marek, D., Pras, E., Nir, U., Reznik-Wolf, H. and Pras, E. (2008) Deleterious mutations in the zinc finger 469 gene cause Brittle Cornea Syndrome. American J Hum. Genet. 82: 1217-1222.
47. Kontorovich, T., Cohen, Y., Nir, U. and Friedman, E. (2009) Promoter methylation patterns of ATM, ATR, BRCA1, BRCA2 and P53 as putative cancer risk modifiers in Jewish BRCA1/BRCA2 mutation carriers. Breast Cancer Research and Treatment 116: 195-200.
48. Cohen, S. , Laitman, Y., Kaufman, B., Milgrom, R., Nir, U., Friedman,E. (2009) SULT1E1 and ID2 genes as candidates for inherited predisposition to breast and ovarian cancer in Jewish women. Fam Cancer. 8: 135-144.
49. Hikri, E., Shpungin, S. and Nir, U. (2009) Hsp90 and a tyrosine embedded in the Hsp90 recognition loop are required for the Fer tyrosine kinase activity. Cell. Signaling. 21:588-596.
50. Hayun, R., Okun, E., Berrebi, A., Shvidel, L., Bassous, L., Sredni, B. and Nir, U. (2009) Rapamycin and Curcumin induce apoptosis in primary resting B chronic lymphocytic leukemia cells. Leukemia and Lymphoma. 50: 625-632.
51. Avraham, G., Volpe, M., Shpungin, S. and Nir, U. (2009) TMF/ARA160 down-regulates pro-angiogenic genes and attenuates the progression of PC3 xenografts. Int. J. Cancer. 125: 43-53.
52. Vardi, A., Anikster, Y., Eisenkraft, A., Shohat, M., Abu-Much, J., Eisenkraft, S., Sredni, B. and Nir, U. (2009) A new genetic isolate of acrodermatitis enteropathica with a novel mutation. British J. Dermatol. 160: 1346-1348.
53. Kontrovich, T., Levy, A., Korostishevsky, M., Nir, U. and Friedman, E. (2010) Single nucleotide polymorphisms in miRNA binding sites and miRNA genes as breast/ovarian cancer risk modifiers in Jewish high-risk women. Int. J. Cancer 127:589-597.
54. Abrham, G., Dovrat, S., Bessler, H., Grossman, S., Nir, U. and Bergman, M. (2010) Inhibition of inflammatory cytokine secretion by plant-derived compounds Inuviscolide and Tomentoxin: The role of NFkB and Stat1. The open pharmacology journal 4:36-44.
55. Lerer-Goldshtein,T., Shpungin, S., Bel, S., Perry, E., Motro, B., Goldstein, R.S., Itach Bar-Sheshet, S., Breitbart, H.and Nir. U. (2010) TMF/ARA160: a key regulator of sperm development. Developmental Biology 348:.12-21.
56. Don, J., Nir, U. and Breitbart, H. (2011) DMRT1 at the border between mitosis and meiosis. Asian J Androl. 13: 189-90.
57. Makovski, A., Yaffe , E. , Shpungin, S. and Nir, U. (2012) Intronic promoter drives the BORIS-regulated expression of FerT in colon carcinoma cells. J.Biol.Chem 24: 6100-6112.
58. Makovski, A., Shpungin, S. and Nir,U. (2012) Down-regulation of Fer induces ROS generation accompanied by ATM and p53 activation in colon carcinoma cells. Cell Signal. 24: 1369-1374.
59. Bel, S., Elkis,Y., Lerer-Goldstein,T., Nyska, A., Shpungin, S., and Nir, U. (2012) Loss of TMF/ARA160 renders the colonic mucus refractory to bacterial colonization and diminishes intestinal susceptibility to acute colitis. J.Biol.Chem 287 : 25631-25639 (With a cover).
60. Elkis, Y., Bel, S., Goldstein –Lerrer, T. , Nyska, A., Creasy, D.M., Shpungin, S. and Nir, U. (2013) Testosterone deficiency accompanied with testicular and epididymal abnormalities in TMF-/- mice. Mol.Cel.Endocrinol. 365: 52-63.
61. Bel, S., Elkis, Y., Lerrer-Goldstein, T., Ban-Horin, S., Niska, A., Shpungin, S. and Nir, U. (2014) Reprogrammed and transmissible microbiota confer diminished susceptibility to induce colitis in TMF-/- mice. Proc.Nat.Acad.Sci.USA 111:4964-4969.
62. Yaffe, E., Hikri, E., Elkis, Y. Cohen, O., Segal, A., Nakovski, A., Varvak, A., Shpungin, S. and Nir, U. (2014) Oncogenic properties of a spermatogenic meiotic variant of Fer kinase expressed in somatic cells. Cancer Res. 74: 6474-6485.
63. Zolberg-Relevy, N., Ruhl, R., Harari, A., Grosskopf, I. , Barshack, I., Ben-Amoz, A., Nir, U., Gottlieb, H., Kamari, Y., Harats, D., and Shaish, A. (2015) 9-cis b-carotene inhibits Atherosclerosis Development in Female LDLR-/- Mice. Functional Foods in Health and Disease 5(2):67-79.
64. Elkis, Y., Bel, S., Shpungin, S. and Nir, U. (2015) TMF/ARA160 governs the spatial Golgi orientation during sperm development. PLos One (Under review).
65. U.S. Patent No. 7,442,781 (2008) "Diagnosis, prevention and treatment of cancer". Inventors: Uri Nir, Erez Perry and Sally Shpungin.
66. PCT US patent application no. IL2007/000360 (2007) "Methods and systems for searching for regulators of the Fer protein and for monitoring the effects of the Fer protein".
Inventors: Uri Nir, Orel Pasder, Sally Shpungin and Etai Yaffe.
Regulation of normal and malignant cell growth. One of the key questions in modern biology is what governs the normal proliferation and life span of mammalian cells and what "goes wrong" in cancer cells. Unraveling these molecular events should lead to a better understanding of the malignant transformation process and to the rational development of novel cancer-therapy approaches. In our lab, we study the involvement of stress response circuits in the adaptation of cells to stress insults and in the growth of cancer cells. Three proteins which "cross-talk" with each other are currently being studied in our lab. The first protein is the intracellular tyrosine kinase Fer. This enzyme resides in both the cytoplasm and nucleus of cells and it supports the withstanding of cells in various stress cues such as oxidative stress and nutrient deprivation. We have recently discovered a previously unknown oncogenic form of Fer which is solely expressed in malignant cells. Specific knock-down of this oncogenic form led to the apoptotic death of the treated cancer cells. Thus, the oncogenic Fer is a novel target for cancer intervention. To translate these findings into the development of a new anti-cancer drug, we developed a yeast-based high-through screening assay which was implemented in a most advanced robotic system. This enabled the development of a highly potent and selective Fer inhibitor that induces apoptotic death in malignant but not in normal cells, and which paves the way for the development of a new anti-cancer drug.
The two other proteins involved in cellular responses to imposed stress regimes are TMF/ARA160 and TRNP. While TRNP supports the survival of cells under defined stress conditions, TMF/ARA160 dictates the onset of cellular death under extended stress insults. TRNP is a nuclear protein that associates with chromatin and is highly expressed in neuronal brain cells. RNA expression analysis using DNA chip arrays, revealed the suppression of pro-apoptotic genes by TRNP. Hence, TRNP is a transcription regulator that supports the survival of neuronal cells. The malfunctioning of TRNP may, therefore, contribute to the onset of neuronal cell death and consequent neurodegenerative diseases. We are currently examining the functioning of TRNP in mice models under normal and pathological conditions.
Finally, we are studying the role of TMF in modulating the response of mammalian cells to genotoxic and metabolic stress. TMF is a Golgi-associated protein. However, under stress conditions, TMF is translocated from the Golgi and is dispersed in the cytoplasm, where it directs key transcription regulators to degradation. This can be carried out by substrate ubiquitination and proteasomal degradation, or by lysosome-mediated degradation in an autophagy-dependent manner. Recently, we have characterized a key role of TMF in the acquired resistance of cancer cells to chemotherapeutic agents. Thus, TMF is a master regulator which modulates the response of cells to stress insults. We are currently devising molecular approaches for manipulating the TMF system and, thereby, restoring the sensitivity of cancer cells to chemotherapeutic treatments.