Baruch Frenkel Associate Professor Biochemistry & Molecular Biology, Orthopedic Surgery Keck School of Medicine Institute for Genetic Medicine

Education:
BSc(honors) 1983 Dental Medicine - Hebrew University Hadassah Faculty of Dental Medicine, Israel
DMD 1986 Dental Medicine - Hebrew University Hadassah Faculty of Dental Medicine, Israel
PhD 1991 Biochemistry - Hebrew University Hadassah Faculty of Medicine

Postdoctoral Research Fellowship:
1991 - 1993 University of Massachusettes Medical Center, Massachusettes

Started at USC: 1997

Research Topics: Cell Cycle, Growth & Proliferation, Signal Transduction, Diabetes/Metabolic Diseases, Gene Regulation/Transcription

Research Description

The bone molecular biology laboratory investigates transcription factors that regulate bone metabolism in health and disease.  These include LEF/TCF, Krox20/EGR2, Runx2, the estrogen receptor (ER) and the androgen receptor (AR).  The first two became of interest based on their involvement in glucocorticoid (GC)-induced osteoporosis (GIO).  By stimulating GSK3ß in osteoblasts (JBC 277:18191, 2002), among other mechanisms, gluccorticois inhibit LEF/TCF-mediated transcription (JBC 280:2388, 2005), contributing to GC-mediated inhibition of osteoblast proliferation, differentiation, and formation of a mineralized exrtacellular matrix (JBC 275:19992, 2000).  Consistent with this, LEF1 haploinsufficiency reduces bone formation and bone mass, especially under conditions of high bone turnover (PLoS One 4:e5438, 2009).  Inhibition of Krox20 by GCs was discovered both by gene expression profiling of dexamethasone-arrested osteoblasts (JME 33:175, 2004) and by identification of Krox20 as the factor transactivating a novel negative GC-response element at the osteoclacin promoter (A&R 52:929, 2005).  Presently, an RO1-funded project is ongoing to assess the role of Krox20 in bone cell growth and differentiation in vitro and in bone metabolism in vivo.

Runx2, a master regulator of bone development and homeostasis, has recently assumed a center stage in the lab.  Earlier studies with a cell culture model of GIO demonstrated Runx2-independent inhibition of osteoblast function by GCs (JBC 278:44995, 2003).  The GC-mediated inhibition of Bmp2 (JBMR 18:1186, 2003), which operates upstream of Runx2 in other contexts, appeared to be a consequence rather than the cause for the adverse effects of GCs (Growth Factors 26:226, 2008).  However, our interest in Runx2 has recently grown with the discovery of its inhibition by ERα (Endocrinol. 149: 5948, 2008) and AR (Mol. Endocrinol., 2009) in osteoblasts.  A new NIH-funded project is designed to evaluate the contribution of these mechanisms to the bone-sparing properties of sex steroids.  Furthermore, estrogens and androgens inhibit Runx2 in breast (Endocrinol. 149: 5948, 2008) and prostate cancer cells (Mol. Endocrinol., 2009), respectively.  We recently added to our skeletal research interests a new line of investigation focusing on hormone carcinogenesis (Mol. Cancer 6:39, 2007; Prostate 67:1371, 2007; PLoS ONE 3: e3645, 2008) and we are currently evaluating the potential role of Runx2 in the pathophysiological and pharmacological effects of sex steroids and selective estrogen receptor modulators not only in bone but also in breast and prostate cancer.

Upcoming Articles:

Baniwal SK et al: Repression of Runx2 by Androgen Receptor (AR) in Osteoblasts and Prostate Cancer Cells: AR Binds Runx2 and Abrogates its Recruitment to DNA. Mol. Endocrinol., in press.

Pomerantz MM et al: The 8q24 cancer risk variant rs6983267 demonstrates long range interaction with MYC in colorectal cancer.  Nature Genetics, in press.

Jia et al: Functional Enhancers at the Gene-Poor 8q24 Cancer-Linked Locus.  PLoS Genetics, in press.