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
MECHANISMS OF GLUCOCORTICOID-INDUCED OSTEOPOROSIS
Glucocorticoids, widely prescribed for the management of autoimmune and inflammatory diseases inhibit osteoblast function and cause osteoporosis, but the underlying mechanisms are not well understood. We have developed an osteoblast tissue culture model, in which glucocorticoids inhibit progression through a defined commitment stage, resulting in >90% inhibition of collagen accumulation and mineralized extracellular matrix formation. Focusing on this commitment stage we have made the following discoveries, each establishing an independent research endeavor:
A. GSK3ß and the Wnt signaling pathway.
We discovered that glucocorticoids inhibit the PI3-kinase/Akt pathway in osteoblasts undergoing commitment and that this inhibition results in activation of glycogen synthase kinase 3ß (GSK3ß). Consequently, GSK3ß substrates such as c-Myc are hyperphosphrylated and degraded, resulting in attenuation of a differentiation-related cell cycle. Inhibition of the PI3-kinase/Akt pathway and the consequent activation of GSK3ß also lead to inhibition of the Wnt signaling pathway, establishing, against the current dogma, the existence of a PI3-kinase/Akt/GSK3ß/b-catenin/LEF axis under certain physiological conditions. Ongoing studies focus on glucocorticoid targets downstream of GSK3ß and the roles that these targets play in bone metabolism in vivo.
B. Egr2/Krox20
While inhibiting osteoblast function, glucocorticoids suppress expression of the osteoblast marker gene, osteocalcin. We discovered that this inhibition occurs via a cis-acting element of the osteoclacin promoter, which specifically binds a transcription factor called Egr2/Krox20, and that Egr2/Krox20 expression is strongly reduced in glucocorticoid-treated osteoblasts. Ongoing studies aim at mechanisms of glucocorticoid-mediated Egr2/Krox20 repression and the contribution of Egr2/Krox20 to the control of bone mass in vivo.
C. Bone morphogenetic protein-2 (Bmp2)
During the osteoblast commitment stage described above, glucocorticoids inhibit the expression of the Bmp2 gene, which has been linked to bone mass in human populations. Recombinant BMP-2 rescues the commitment-associated cell cycle and mineralization in glucocorticoid-treated osteoblast cultures. Current studies aim at mechanisms underlying the glucocorticoid-mediated repression of Bmp2.
RUNX2 TARGET GENES IN OSTEOBLASTS
Runx2 (a.k.a. Cbfa1 and AML3) is a master transcription factor in osteoblast differentiation. However, it is difficult to explain the function of Runx2 based on its known target genes. We have developed Chromatin Immunoprecipitation (ChIP) Display (CD), a method by which we have already discovered four novel Runx2 target genes in osteoblasts. We are continuing to use CD, as well as alternative methods, to discover additional Runx2 target genes in osteoblasts, and we are testing the role of these genes in osteoblast differentiation and bone formation.
ANDROGEN RECEPTOR AND RUNX2 IN PROSTATE CANCER
The role of the androgen receptor (AR) in prostate cancer initiation and progression is well established. However, as for Runx2 in osteoblasts, there is only limited knowledge of AR target genes that may mediate its role in prostate cancer. We therefore employ ChIP Display to discover AR target genes in prostate cancer cells.
Interestingly, Runx2, otherwise an osteoblast master transcription factor, is ectopically expressed in prostate cancer cells, potentially contributing to the tendency of these cells to metastasize to bone. In addition, Runx2 has been shown to interact with the AR. Therefore, we are also pursuing Runx2 targets genes and investigating mechanisms by which Runx2 contributes to prostate cancer progression.
OSTEOGENIC GROWTH PEPTIDE (OGP)
We are interested in OGP, an alternative translation product of histone H4 genes. OGP is synthesized by translational initiation at the Met85 codon of histone H4. This is facilitated by leaky ribosomal scanning (LRS) through the imperfect canonical initiation codon of H4 genes. Such a mechanism of alternative translation likely occurs in as much as 12% of mammalian genes. In the case of H4, the LRS and the alternative translation of OGP results in increased bone mass. We have demonstrated the mechanism of OGP biosynthesis in tissue culture and addressed the physiological outcome of this phenomenon using transgenic mice. Current studies focus on the mechanisms of action of OGP in bone.
Selected Publications
Barski A, Pregizer S, Frenkel B. - Identification of Transcription Factor Target Genes by ChIP Display. - Methods Mol Biol [ 2008 ] 455:177-90 . PubMed
Zhou B, Zhong Q, Minoo P, Li C, Ann D, Frenkel B, Morrisey EE, Crandall ED, Borok Z. - Foxp2 Inhibits Nkx2.1-mediated Transcription of SP-C via Interactions with the Nkx2.1 Homeodomain. - Am J Respir Cell Mol Biol [ 2008 ] Jan 31; . PubMed
Yang S, Pham LK, Liao CP, Frenkel B, Reddi AH, Roy-Burman P. - A novel bone morphogenetic protein signaling in heterotypic cell interactions in prostate cancer. - Cancer Res [ 2008 ] Jan 1;68(1):198-205 . PubMed
Leclerc N, Noh T, Cogan J, Samarawickrama DB, Smith E, Frenkel B. - Opposing effects of glucocorticoids and Wnt signaling on Krox20 and mineral deposition in osteoblast cultures. - J Cell Biochem [ 2008 ] Apr 15;103(6):1938-51 . PubMed
Prescott J, Jariwala U, Jia L, Cogan JP, Barski A, Pregizer S, Shen HC, Arasheben A, Neilson JJ, Frenkel B, Coetzee GA. - Androgen receptor-mediated repression of novel target genes. - Prostate [ 2007 ] Sep 15;67(13):1371-83 . PubMed
Jariwala U, Prescott J, Jia L, Barski A, Pregizer S, Cogan JP, Arasheben A, Tilley WD, Scher HI, Gerald WL, Buchanan G, Coetzee GA, Frenkel B. - Identification of novel androgen receptor target genes in prostate cancer. - Mol Cancer [ 2007 ] Jun 6;6:39 . PubMed
Pregizer S, Barski A, Gersbach CA, García AJ, Frenkel B. - Identification of novel Runx2 targets in osteoblasts: cell type-specific BMP-dependent regulation of Tram2. - J Cell Biochem [ 2007 ] Dec 15;102(6):1458-71 . PubMed
Zhu W, Boachie-Adjei O, Rawlins BA, Frenkel B, Boskey AL, Ivashkiv LB, Blobel CP. - A novel regulatory role for stromal-derived factor-1 signaling in bone morphogenic protein-2 osteogenic differentiation of mesenchymal C2C12 cells. - J Biol Chem [ 2007 ] Jun 29;282(26):18676-85 . PubMed
Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I. - Peripheral cannabinoid receptor, CB2, regulates bone mass. - Proc Natl Acad Sci U S A [ 2006 ] Jan 17;103(3):696-701 . PubMed
Miguel SM, Namdar-Attar M, Noh T, Frenkel B, Bab I. - ERK1/2-activated de novo Mapkapk2 synthesis is essential for osteogenic growth peptide mitogenic signaling in osteoblastic cells. - J Biol Chem [ 2005 ] Nov 11;280(45):37495-502 . PubMed
