Professor, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University
Lady Davis Chair in Biochemistry
Chair, Department of Human Molecular Genetics and Biochemistry
Head, Yoran Institute for Human Genome Research
Education
| 1971-1974 | B.Sc., Department of Biology | Hebrew University, Jerusalem |
| 1974-1977 | M.Sc., Department of Genetics | Hebrew University, Jerusalem |
| 1982-1987 | Ph.D., Department of Hormone Research | Weizmann Institute of Science, Rehovot |
| 1987-1990 | Post-doctoral Fellow, Diabetes Branch | National Institutes of Health, Bethesda, MD, USA |
Molecular Biology of the Insulin-Like Growth Factor System
The insulin-like growth factors (IGF1, IGF2) are a family of hormones with important roles in growth and development. The biological actions of the IGFs are mediated by the IGF1 receptor (IGF1R), a cell-surface receptor related to the insulin receptor. The IGF1R signaling pathway has an important role in the biochemical chain of events linking obesity, diabetes, and cancer. Our work is aimed at understanding the molecular and cellular events responsible for IGF1R expression in cancer. These studies are expected to generate information that might translate into more efficient IGF1R targeting approaches. Furthermore, a better understanding of the molecular biology of the IGF system will have important ramifications in areas such as obesity, metabolic syndrome, diabetes, and cancer research. Specific topics include:
Articles
Schayek, H., Bentov, I., Rotem, I., Pasmanik-Chor, M., Ginsberg, D., Plymate, S.R. and Werner, H. (2010) Transcription factor E2F1 is a potent transactivator of the insulin-like growth factor-I receptor gene. Growth Hormone & IGF Res. 20:68-72.
Rubovitch, V., Edut, S., Sarfstein, R., Werner, H. and Pick C.G. (2010) The intricate involvement of the insulin-like growth factor receptor signaling in mild traumatic brain injury in mice. Neurobiol Dis. 38:299-303.
Sarfstein, R., Belfiore, A. and Werner, H. (2010) Identification of IGF-I receptor gene promoter-binding proteins in estrogen receptor (ER)-positive and ER-depleted breast cancer cells. Cancers (Basel) 2:233-261.
Aiello, A., Pandini, G., Sarfstein, R., Werner, H., Manfioletti, G., Vigneri, R. and Belfiore, A. (2010) HMGA1 protein is a positive regulator of the insulin-like growth factor-I receptor gene. Eur J Cancer 46:1919-1926.
Schayek, H., Bentov, I., Sun, S., Plymate, S.R. and Werner, H. (2010) Progression to metastatic stage in a cellular model of prostate cancer is associated with methylation of the androgen receptor gene and transcriptional suppression of the insulin-like growth factor-I receptor gene. Exp Cell Res. 316:1479-1488.
Schayek, H., Seti, H., Greenberg, N., Sun, S., Werner, H. and Plymate, S.R. (2010) Differential regulation of insulin-like growth factor-I receptor gene expression by wild-type and mutant androgen receptor in prostate cancer cells. Mol Cell Endocrinol. 323:239-245.
Bruchim, I., Amichay, K., Kidron, D., Attias, Z. Biron-Shental, T., Drucker, L., Friedman, E., Werner, H. and Fishman, A. (2010) BRCA-1/2 germline mutations in Jewish patients with uterine serous carcinoma. Int J Gynecol Cancer 20:1148-1153.
Werner, H. and Bruchim, I. (2010) Basic and clinical significance of IGF-I-induced signatures in cancer. BMC Medicine Jan 5; 8:2.
Yehezkel, E., Weinstein, D., Simon, M., Sarfstein, R., Laron, Z. and Werner, H. (2010) Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor. Diabetologia 53:2667-2675.
Attias-Geva, Z., Bentov, I., Fishman, A., Werner, H. and Bruchim, I. (2011) Insulin-like growth factor-I receptor inhibition by specific tyrosine kinase inhibitor NVP-AEW541 in endometrioid and serous papillary endometrial cancer cell lines. Gynecol Oncol. 121:383-389.
Attias-Geva, Z., Bentov, I., Ludwig, D.L., Fishman, A., Bruchim, I. and Werner, H. (2011) Insulin-like growth factor-I receptor targeting with monoclonal antibody cixutumumab (IMC-A12) inhibits IGF-1 action in endometrial cancer cells. Eur J Cancer 47:1717-1726.
Rubovitch, V., Shachar, A., Werner, H. and Pick, C. (2011) Does IGF-1 administration after a mild traumatic brain injury in mice activate the adaptive arm of ER stress? Neurochem Int 58:443-446.
Werner, H. and Chantelau, E. (2011) Differences in bioactivity between human insulin and insulin analogues approved for therapeutic use – compilation of reports from the past 20 years. Diabetol Metab Syndr 29, 3:13.
Sarfstein, R., Bruchim, I., Fishman, A. and Werner, H. (2011) The mechanism of action of the histone deacetylase inhibitor vorinostat involves interactions with the insulin-like growth factor signaling pathway. PLoS One, 6:e24468.
Attias-Geva, Z., Bentov, I., Kidron, D., Amichay, K., Sarfstein, R., Fishman, A., Bruchim, I. and Werner, H. (2011) p53 regulates IGF-I receptor gene expression in uterine serous carcinoma and predicts responsiveness to an IGF-IR-directed targeted therapy. Eur J Cancer, 4:1570-1580.
Sarfstein, R., Pasmanik-Chor, M., Yeheskel, A., Edry, L., Shomron, N., Warman, N., Wertheimer, E., Maor, S., Shochat, L. and Werner, H. (2012) Insulin-like growth factor-I receptor (IGF-IR) translocates to nucleus and autoregulates IGF-IR gene expression in breast cancer cells. J Biol Chem. 287:2766-2776.
Amichay, K., Kidron, D., Attias-Geva, Z., Schayek, H., Sarfstein, R., Fishman, A., Werner, H. and Bruchim, I. (2012) BRCA1 is expressed in uterine serous carcinoma (USC) and controls insulin-like growth factor-I receptor (IGF-IR) gene expression in USC cell lines. Int J Gynecol Cancer 22:748-754.
Schayek, H., Bentov, I., Jacob-Hirsch, J., Yeung, C., Khanna, C., Helman, L.J., Plymate, S.R. and Werner, H. (2012) Global methylation analysis identifies PITX2 as an upstream regulator of the androgen receptor and IGF-I receptor genes in prostate cancer. Hormone Metab Res. 44:511-519.
Sarfstein, R., Friedman, Y., Attias-Geva, Z., Fishman, A., Bruchim, I. and Werner, H. (2013) Metformin down-regulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma cells proliferation and migration in p53-dependent or -independent manners. PLoS One 8:e61537.
Bitelman, C., Sarfstein, R., Sarig, M., Attias-Geva, Z., Fishman, A., Werner, H. and Bruchim, I. (2013) IGF1R-directed targeted therapy enhances the cytotoxic effect of chemotherapy in endometrial cancer. Cancer Lett. 335:153-159.
Hermani, A., Shukla, A., Medunjanin, S., Werner, H. and Mayer, D. (2013) Insulin-like growth factor binding protein-4 and -5 modulate ligand-dependent estrogen receptor-a activation in breast cancer cells in an IGF-independent manner. Cell Signal. 25:1395-1402.
Weinstein, D., Sarfstein, R., Laron, Z. and Werner, H. (2014) Insulin receptor compensates for IGF1R inhibition and directly induces mitogenic activity in prostate cancer cells. Endocrine Connect. 3:24-35.
Canetti, L., Werner, H. and Leikin-Frenkel, A. (2014) Linoleic and alpha-linolenic acids ameliorate streptozotocin-induced diabetes in mice. Arc. Physiol Biochem. 120:34-39.
Rubinfeld, H., Kammer, A., Cohen, O., Gorshtein, A., Cohen, Z.R., Hadani, M., Werner, H. and Shimon, I. (2014) IGF1 induces cell proliferation in human pituitary tumors – Functional blockade of IGF1 receptor as a novel therapeutic approach in non-functioning tumors. Mol Cell Endocrinol. 390:93-101.
Bruchim, I., Sarfstein, R., Reiss, A., Flescher, E. and Werner, H. (2014) IGF1R tyrosine kinase inhibitor enhances the cytotoxic effect of methyl jasmonate in endometrial cancer. Cancer Lett. 352:214-219.
Aizen, D., Sarfstein, R., Bruchim, I., Weinstein, D., Laron, Z. and Werner, H. (2015) Proliferative and signaling activities of insulin analogues in endometrial cancer cells. Mol. Cell. Endocrinol. 406:27-39.
Solomon-Zemler, R., Weingarten, G., Sarfstein, R., Laron, Z., Werner, H. and Wertheimer, E. (2015) Insulin analogues display atypical differentiative activities in skin keratinocytes. Arch. Physiol. Biochem., 121:32-39.
Milanesi, E., Hadar, A., Maffioletti, E., Werner, H., Shomron, N., Gennarelli, M., Schulze, T., Costa, M., Del Zompo, M., Squassina, A. and Gurwitz, D. (2015) IGF-1 differentially affects lithium sensitivity of lymphoblastoid cell lines from lithium responder and non-responder bipolar disorder patients. J. Mol. Neurosci., 56:681-687.
Shinderman Maman, E., Cohen, K., Weingarten, C., Nabriski, D., Twito, O., Baraf, L., Hercbergs, A., Davis, P.J., Werner, H., Ellis, M. and Ashur-Fabian, O. (2016) The thyroid hormone-avb3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation. Oncogene 35:1977-1987.
Lapkina-Gendler, L., Rotem, I., Pasmanik-Chor, M., Gurwitz, D., Sarfstein, R., Laron, Z. and Werner, H. (2016) Identification of signaling pathways associated with cancer protection in Laron syndrome. Endocrine Related Cancer 23:399-410.
Meisel-Sharon, S., Pozniak, Y., Geiger, T. and Werner,H. (2016) TMPRSS2-ERG fusion protein regulates insulin-like growth factor-1 receptor (IGF1R) gene expression in prostate cancer: involvement of transcription factor Sp1. Oncotarget, in press.
Reviews
Werner, H., Weinstein, D., Yehezkel, E. and Laron, Z. (2011) Controversies in the use of insulin analogues. Expert Opinion Biol Ther. 11:199-209.
Werner, H. (2011) Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer. Oncogene 31:2703-2714.
Werner, H. and Bruchim, I. (2012) Convergence of the IGF-1 and BRCA1 signaling pathways in familial cancer. Lancet Oncology, 13:E537-544.
Werner, H., Attias-Geva, Z., Bentov, I., Sarfstein, R., Schayek, H., Weinstein, D. and Bruchim, I. (2012) Cancer genes, tumor suppressors, and regulation of IGF-1R gene expression in cancer. In: Insulin-like growth factors and cancer: from basic biology to therapeutics, ed. by LeRoith, D., Springer Science, New York, pp.159-177.
Bentov, I. and Werner, H. (2013) Insulin-like growth factor-1. In: Handbook of Biologically Active Peptides, Second edition, ed. by Kastin, A., Elsevier Press, San Diego. pp. 1627-1632.
Werner, H. and Sarfstein, R. (2013) Insulin receptor family. In: The Receptor Tyrosine Kinase Handbook, ed. by Wheeler, D.L. and Yarden, Y., Springer Science, New York, in press.
Werner, H. (2012) Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer. Oncogene 31:2703-2714.
Bruchim, I. and Werner, H. (2013) Targeting IGF-I signaling pathwys in gynecologic malignancies. Expert Opinion Ther Targets. 17:307-320.
Sarfstein, R. and Werner, H. (2013) Nuclear insulin and insulin-like growth factor receptors: a novel paradigm in signal transduction. Endocrinology 154:1672-1679.
LeRoith, D. and Werner, H. (2014) Insulin and IGF1 receptors in the brain: Physiological and pathological aspects. Eur. Neuropsychopharmacol. 24:1947-1953.
Bruchim, I., Sarfstein, R. and Werner, H. (2014) The IGF hormonal network in endometrial cancer: functions, regulation, and targeting approaches. Front Endocrinol. 5:76.
Werner, H. and Sarfstein, R. (2014) Transcriptional and epigenetic control of IGF1 receptor gene expression: implications in metabolism and cancer. Growth Hormone & IGF Res., 24:112-118.
Werner, H., Sarfstein, R., LeRoith, D. and Bruchim, I. (2016) Insulin-like growth factor-1 (IGF1) signaling axis meets p53 genome protection pathways. Front. Oncol. 6:159.
Laron, Z., Kauli, R., Lapkina, L. and Werner, H. (2016) IGF-1 deficiency, longevity and cancer protection of patients with Laron syndrome. Mutation Res. Rev., in press.
