Department Affiliation(s)

Primary: School of Dentistry

Biographical Sketch
Government. College Sahiwal	BSc	1987	Botany, Zoology Chemistry, Geography
University of the Punjab, Lahore	MSc	1990	Cell Biology
University of the Punjab, Lahore and UMASS Medical. School, Worcester, MA	PhD	2000	Cell & Molecular Biology

	Society Memberships	Current Position	URL
N/A

Research/Clinical Interest Title

Research/Clinical Interest Description

Our laboratory is focused on experimentally understanding the molecular mechanisms involved in formation, and remodeling of skeleton and bone repair. Runt related gene 2 (Runx2), also known as core binding factor a1 (Cbfa1) is an essential transcription factor for osteoblast differentiation and bone formation. Runx2 deficient mice display a complete lack of both intramembranous and endochondral ossification and show a failure of osteoblast differentiation. Targeted mutations disrupting genes by homologous recombination in embryonic stem cells are permanent and can result in a loss of gene function early in embryogenesis, thereby precluding further analysis during post-natal development and in the adults. Both the Runx2 null and knock-in mouse models exhibit perinatal and embryonic lethality respectively. Thus further characterization of specific roles of this gene during post-natal bone formation, bone remodeling, bone repair and aging has not to date been possible. We postulate that Runx2 remains as the master switch of early commitment to the osteogenic lineage, a regulator of osteoblast differentiation, and continues to function in the adult skeleton. Runx2 protein appears to have several selective functions during skeletal development in regulating the osteogenic cell lineage differentiation. To uncover precise functional activities of Runx2 in the postnatal and adult animal we have established conditional Runx2 mouse model. The regulated Cre-LoxP mediated deletion of Runx2 gene in a time and tissue specific manner will provides us a platform to utilize functional genomics for understanding mechanistic linkage between the Runx2 transcription factor and postnatal skeletogenesis.

Postdoc Positions Available

N/A

	Selected Publications  24	PubMed ID
Tang L, Guo B, Javed A, Choi JY, Hiebert S, Lian JB, van Wijnen AJ, Stein JL, Stein GS, Zhou GW. “Crystal structure of the nuclear matrix targeting signal of the transcription factor acute myelogenous leukemia-1/polyoma enhancer-binding protein 2alphaB/core binding factor alpha2”. J Biol Chem 1999, 274:33580-33586. Javed A, Guo B, Hiebert S, Choi JY, Green J, Zhao SC, Osborne MA, Stifani S, Stein JL, Lian JB, van Wijnen AJ, Stein GS. “Groucho/TLE/R-esp proteins associate with the nuclear matrix and repress RUNX (CBF?/AML/PEBP2?) dependent activation of tissue-specific gene transcription”. J Cell Sci 2000, 113:2221-2231. Javed A, Barnes GL, Jasanya BO, Stein JL, Gerstenfeld L, Lian JB, Stein GS. “runt homology domain transcription factors (Runx, Cbfa, and AML) mediate repression of the bone sialoprotein promoter: Evidence for promoter context-dependent activity of Cbfa proteins”. Mol Cell Biol 2001, 21:2891-2905. Choi JY, Pratap J, Javed A, Zaidi SK, Xing L, Balint E, Dalamangas S, Boyce B, van Wijnen AJ, Lian JB, Stein JL, Jones SN, Stein GS. “Subnuclear targeting of Runx/Cbfa/AML factors is essential for tissue-specific differentiation during embryonic development”. Proc Natl Acad Sci USA 2001, 98:8650-8655. Banerjee C, Javed A, Choi JY, Green J, Rosen V, van Wijnen AJ, Stein JL, Lian JB, Stein GS. “Differential regulation of the two principal Runx2/Cbfa1 n-terminal isoforms in response to bone morphogenetic protein-2 during development of the osteoblast phenotype”. Endocrinology 2001, 142:4026-4039. Zaidi SK, Javed A, Choi JY, van Wijnen AJ, Stein JL, Lian JB, Stein GS. “A specific targeting signal directs Runx2/Cbfa1 to subnuclear domains and contributes to transactivation of the osteocalcin gene”. J Cell Sci 2001, 114:3093-3102. Gutierrez S, Javed A, Tennant DK, van Rees M, Montecino M, Stein GS, Stein JL, Lian JB. “CCAAT/enhancer-binding proteins (C/EBP) beta and delta activate osteocalcin gene transcription and synergize with Runx2 at the C/EBP element to regulate bone-specific expression”. J Biol Chem 2002, 277:1316-1323. Harrington SK, Javed A, Drissi H, McNeil S, Lian JB, Stein JL, van Wijnen AJ, Wang YL, Stein GS. “Transcription factors RUNX1/AML1 and RUNX2/Cbfa1 dynamically associate with stationary subnuclear domains”. J Cell Sci 2002, 115:4167-4176. Kundu M, Javed A, Jeon JP, Horner A, Shum L, Eckhaus M, Muenke M, Lian JB, Yang Y, Nuckolls GH, Stein GS, Liu PP. “Cbfbeta interacts with Runx2 and has a critical role in bone development”. Nat Genet 2002, 32(4):639-644. Barnes GL, Javed A, Waller SM, Kamal MH, Hebert KE, Hassan MQ, Bellahcene A, Van Wijnen AJ, Young MF, Lian JB, Stein GS, Gerstenfeld LC. “Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialo protein in human metastatic breast cancer cells”. Cancer Res. 2003 May 15;63(10):2631-2637. Stein GS, Zaidi K, Braastad CD, Montecino M, van Wijnen AJ, Choi JY, Stein JL, Lian JB, Javed A. “Functional architecture of the nucleus: organizing the regulatory machinery for gene expression, replication and repair”. Trends in Cell Biology 2003 November 13(11):584-592. Zaidi K, Young D, Pockwinse S, Javed A, Lian JB, Stein JL, van Wijnen AJ, Stein GS. “Mitotic partitioning of the tissue specific Runx/Cbfa/AML transcription factor to progeny cells”. Proc Natl Acad Sci USA 2003 Dec 9; 100(25):14852-14857. Lian JB, Javed A, Zaidi K, Lengner CJ, Montecino M, van Wijnen AJ, Stein JL, Stein GS. “Regulatory controls for osteoblast growth and differentiation: Role of Runx/Cbfa/AML factors”. Cric. Rev. in Euk. Gene Exp. 2004 14(1&2):1-41. Barnes GL, Hebert KE, Kamal MH, Javed A, Einhorn AT, Lian JB, Stein GS, Gerstenfeld LC. “Fidelity of Runx2 activity in breast cancer cells is required for the generation of metastasis associated osteolytic disease”. Cancer Res. 2004 July 1; 64 (13): 4506-4513. Javed A, Zaidi SK, Gutierrez SE, Lengner CJ, Harrington KS, Hovhannisyan H, Cho BC, Pratap J, Pockwinse SM, Montecino M, van Wijnen AJ, Lian JB, Stein JL, Stein GS. “In situ immunofluorescence analysis: immunofluorescence microscopy”. Methods Mol Biol. 2004;285:23-28. Gutierrez S, Liu J, Javed A, Montecino M, Stein GS, Lian JB, Stein JL. “The vitamin D response element in the distal osteocalcin promoter contributes to chromatin organization of the proximal regulatory domain”. J Biol Chem. 2004 Oct 15;279(42):43581-43588. Hassan MQ, Javed A, Morasso MI, Karlin J, Montecino M, van Wijnen AJ, Stein GS, Stein JL, Lian JB. “Dlx3 transcriptional regulation of osteoblast differentiation: temporal recruitment of Msx2, Dlx3, and Dlx5 homeodomain proteins to chromatin of the osteocalcin gene”. Mol Cell Biol. 2004 Oct;24(20):9248-9261. Afzal F, Pratap J, Ito K, Ito Y, Stein JL, van Wijnen AJ, Stein GS, Lian JB, Javed A. “Smad function and intranuclear targeting share a Runx2 motif required for osteogenic lineage induction and BMP2 responsive transcription”. J Cell Physiol. 2005 July 203(4):604-610. Javed A, Barnes GL, Pratap J, Antkowiak T, Gerstenfeld LC, van Wijnen AJ, Stein JL, Lian JB, Stein GS. “Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo”. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1454-9. Stein GS, Lian JB, Montecino M, van Wijnen AJ, Stein JL, Javed A, Zaidi K. “Involvement of Nuclear Architecture in Regulating Gene Expression in Bone Cells”. Principles of Bone Biology. 2001, Second Edition (Bilezikian J, Raisz L, Rodan G, eds), Academic Press, San Diego, Vol 1, pp 169-200.
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Date Updated

03-11-04

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