Dr. Amjad Javed
Amjad Javed, PhD
Associate Professor
Institute of Oral Health Research
Oral & Maxillofacial Surgery
1919 Seventh Avenue South, Suite SDB 714
Birmingham
,
Phone: 205.996.5124 Fax: 205.996.5109
E-mail:
LAB RESEARCH FOCUS: Genetic Control of Skeleton Formation and Remodeling During Development and Aging
The central focus of our laboratory is to understand the molecular mechanisms that govern the formation and remodeling of skeletal tissues such as Cartilage, Bone, Teeth and Tendon. Cellular differentiation involves the stepwise establishment of specific genetic programs in proliferating cell lineages. We are exploring the signalling role of runt related transcription factor (Runx), in the coordinated regulation of various cell types (Chondrocyte, Osteoblast, Odontoblast) during skeletogenesis. Runx factors are heterodimers formed by α and β subunit and are essential for embryonic development. In mammals three genes encode α subunits (Runx1, 2 and 3) that heterodimerise with the common β subunit. All three gene products recognize the same DNA sequences, but exhibit distinct and non-redundant biological functions. Runx1 is required for definitive hematopoiesis and is frequently mutated in human leukemia. Runx2 is required for osteogenesis and in human mutations of the Runx2 gene are associated with cleidocranial dysplasia, an autosomal dominant skeletal disorder characterized by clavicular and pelvic anomalies, multiple supernumerary teeth, and a sever delay in closure of the fontanels. Runx3 controls neurogenesis, development and proliferation of the gastric epithelium and is frequently silenced in human gastric cancer.
Throughout our life, bone is constantly renewed via a two-part process called remodeling. This process consists of bone resorption and bone formation. During resorption, old bone tissue is broken down and removed by special cells called osteoclasts. During bone formation, new bone tissue is laid down to replace the old. This task is performed by special cells called osteoblasts. Osteoclast and osteoblast function is regulated by several genes and hormones such as calcitonin, parathyroid hormone, vitamin D, estrogen (in women) and testosterone (in men), among others. Runx2 transcription factor is required for normal differentiation and hormonal responsiveness of the Ostoblasts. Our lab utilizes biochemical, cellular, genetic and molecular approaches to identify molecular pathways that conveys osteogenic signal to Runx2 for formation and activity of bone cell.
Runx2 knock-in and knock-out mouse models show a complete absence of both intramembranous and endochondral ossification and dies in utero or shortly after birth.
Because of embryonic lethality current models are useless to address Runx2 role in bone formation, remodeling and repair in adults. To circumvent this difficulty we have developed mouse model where Runx2 gene can be inactivated in adults in a spatio-temporal fashion. We are directing our efforts towards understanding of specific roles of Runx2 gene during post-natal bone formation, bone remodeling, fracture healing, osteoporosis, autoimmune diseases (lupus, psoriasis, rheumatoid arthritis) and aging.
Lab rotation projects: Number of projects that can be developed into MS and Ph.D. thesis are available in the area of transcription regulation, molecular signaling, cellular differentiation and skeletal development. Projects utilize transgenic, knock-out mice, primary & tumor cell and organ culture models.
Selected Publications (PubMed for Dr. Amjad Javed):
· Javed A, Gutierrez S, Montecino M, van Wijnen AJ, Stein JL, Stein GS, Lian JB. “Multiple Cbfa/AML sites in the rat osteocalcin promoter are required for basal and vitamin D-responsive transcription and contribute to chromatin organization”. Mol. Cell. Biol. 1999, 19(11):7491-7500 Entrez PubMed
· 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(alpha)/AML/PEBP2(alpha)) dependent activation of tissue-specific gene transcription”. J. Cell. Sci. 2000, 113:2221-2231. Entrez PubMed
· 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(8):2891-2905. Entrez PubMed
· 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, Sep;142(9):4026-4039. Entrez PubMed
· 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(2):1316-1323. Entrez PubMed
· 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. Entrez PubMed
· Harrington KS, 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, Nov 1;115(Pt 21):4167-4176. Entrez PubMed
· Stein GS, Zaidi SK, 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 13(11):584-592. Entrez PubMed
· 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. “Protein-deoxyribonucleic acid interactions linked to gene expression: DNase I digestion”. Methods Mol Bio. 2004;285:57-62. Entrez PubMed
· 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 factor in breast cancer cells inhibits osteolysis in vivo”. PNAS. 2005 102(5):1454-1459. Entrez PubMed
· 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 204(1):63-72. Entrez PubMed
· Li X, Vradii D, Gutierrez S, Lian JB, van Wijnen AJ, Stein JL, Stein GS, Javed A. “Subnuclear targeting of Runx1 is required for synergistic activation of the myeloid specific M-CSF receptor promoter by PU.1”. J. Cell. Biochem. 2005 7;96(4):795-809. Entrez PubMed
· Bae JS, Gutierrez S, Narla R, Pratap J, Devados R, Stein JL., Stein GS, Lian JB, Javed A. “Reconstitution of Runx2/Cbfa1 null cells identifies Runx2 functional domains required for osteoblast differentiation”. J. Cell. Biochem. 2006 Feb 1;100(2):434-49. Entrez PubMed
· Young DW, Hassan MQ, Pratap J, Galindo M, Zaidi SK, Lee SH, Yang X, Xie R, Javed A, Underwood JM, Furcinitti P, Imbalzano AN, Penman S, Nickerson JA, Montecino MA, Lian JB, Stein JL, van Wijnen AJ, Stein GS. “Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2”. Nature. 2007 Jan 25;445(7126):442-446 Entrez PubMed
· Zaidi SK, Young DW, Javed A, Pratap J, Montecino M, van Wijnen A, Lian JB, Stein JL, Stein GS. “Nuclear microenvironments in biological control and cancer”. Nature Rev Cancer. 2007 Jun;7(6):454-463. Entrez PubMed