J L Stein

University of Massachusetts Medical School, Worcester, MA, United States

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Publications (226)1089.66 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Three parameters of nuclear structure contribute to transcriptional control. The linear representation of promoter elements provides competency for physiological responsiveness within the contexts of developmental as well as cell cycle and phenotype-dependent regulation. Chromatin structure and nucleosome organization reduce distances between independent regulatory elements providing a basis for integrating components of transcriptional control. The nuclear matrix supports gene expression by imposing physical constraints on chromatin related to three dimensional genomic organization. In addition, the nuclear matrix facilitates gene localization as well as the concentration and targeting of transcription factors. Several lines of evidence are presented which are consistent with involvement of multiple levels of nuclear architecture in cell growth and tissue-specific gene expression during differentiation. Growth factor and steroid hormone responsive modifications in chromatin structure, nucleosome organization and the nuclear matrix are considered which influence transcription of the cell cycle regulated histone gene and the bone tissue-specific osteocalcin gene during progressive expression of the osteoblast phenotype.
    07/2011: pages 57-82;
  • Stem Cells: From Bench to Bedside,. 01/2010;
  • Bone 01/2010; 47. · 3.82 Impact Factor
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    ABSTRACT: Runx2, a bone-specific transcriptional regulator, is abnormally expressed in highly metastatic prostate cancer cells. Here, we identified the functional activities of Runx2 in facilitating tumor growth and osteolysis. Our studies show that negligible Runx2 is found in normal prostate epithelial and non-metastatic LNCaP prostate cancer cells. In the intra-tibial metastasis model, high Runx2 levels are associated with development of large tumors, increased expression of metastasis-related genes (MMP9, MMP13, VEGF, Osteopontin) and secreted bone-resorbing factors (PTHrP, IL8) promoting osteolytic disease. Runx2 siRNA treatment of PC3 cells decreased cell migration and invasion through Matrigel in vitro, and in vivo shRunx2 expression in PC3 cells blocked their ability to survive in the bone microenvironment. Mechanisms of Runx2 function were identified in co-culture studies showing that PC3 cells promote osteoclastogenesis and inhibit osteoblast activity. The clinical significance of these findings is supported by human tissue microarray studies of prostate tumors at stages of cancer progression, in which Runx2 is expressed in both adenocarcinomas and metastatic tumors. Together these findings indicate that Runx2 is a key regulator of events associated with prostate cancer metastatic bone disease.
    Oncogene 11/2009; 29(6):811-21. · 7.36 Impact Factor
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    ABSTRACT: The three mammalian Runt homology domain transcription factors (Runx1, Runx2, Runx3) support biological control by functioning as master regulatory genes for the differentiation of distinct tissues. Runx proteins also function as cell context-dependent tumor suppressors or oncogenes. Abnormalities in Runx mediated gene expression are linked to cell transformation and tumor progression. Runx2 is expressed in mesenchymal linage cells committed to the osteoblast phenotype and is essential for bone formation. This skeletal transcription factor is aberrantly expressed at high levels in breast and prostate tumors and cells that aggressively metastasize to the bone environment. In cancer cells, Runx2 activates expression of bone matrix and adhesion proteins, matrix metalloproteinases and angiogenic factors that have long been associated with metastasis. In addition, Runx2 mediates the responses of cells to signaling pathways hyperactive in tumors, including BMP/TGFbeta and other growth factor signals. Runx2 forms co-regulatory complexes with Smads and other co-activator and co-repressor proteins that are organized in subnuclear domains to regulate gene transcription. These activities of Runx2 contribute to tumor growth in bone and the accompanying osteolytic disease, established by interfering with Runx2 functions in metastatic breast cancer cells. Inhibition of Runx2 in MDA-MB-231 cells transplanted to bone decreased tumorigenesis and prevented osteolysis. This review evaluates evidence that Runx2 regulates early metastatic events in breast and prostate cancers, tumor growth, and osteolytic bone disease. Consideration is given to the potential for inhibition of this transcription factor as a therapeutic strategy upstream of the regulatory events contributing to the complexity of metastasis to bone.
    Cancer and metastasis reviews 01/2007; 25(4):589-600. · 7.79 Impact Factor
  • Bone 01/2006; 38(3):34-34. · 3.82 Impact Factor
  • Cancer research. 01/2003; 63(17):5357.
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    ABSTRACT: Cbfa1/Runx2 is a transcription factor essential for bone formation and osteoblast differentiation. Two major N-terminal isoforms of Cbfa1, designated type I/p56 (PEBP2aA1, starting with the sequence MRIPV) and type II/p57 (til-1, starting with the sequence MASNS), each regulated by distinct promoters, are known. Here, we show that the type I transcript is constitutively expressed in nonosseous mesenchymal tissues and in osteoblast progenitor cells. Cbfa1 type I isoform expression does not change with the differentiation status of the cells. In contrast, the type II transcript is increased during differentiation of primary osteoblasts and is induced in osteoprogenitors and in premyoblast C2C12 cells in response to bone morphogenetic protein-2. The functional equivalence of the two isoforms in activation and repression of bone-specific genes indicates overlapping functional roles. The presence of the ubiquitous type I isoform in nonosseous cells and before bone morphogenetic protein-2 induced expression of the type II isoform suggests a regulatory role for Cbfa1 type I in early stages of mesenchymal cell development, whereas type II is necessary for osteogenesis and maintenance of the osteoblast phenotype. Our data indicate that Cbfa1 function is regulated by transcription, cellular protein levels, and DNA binding activity during osteoblast differentiation. Taken together, our studies suggest that developmental timing and cell type- specific expression of type I and type II Cbfa isoforms, and not necessarily molecular properties or sequences that reside in the N-terminus of Cbfa1, are the principal determinants of the osteogenic activity of Cbfa1.
    Endocrinology 10/2001; 142(9):4026-39. · 4.72 Impact Factor
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    ABSTRACT: Regulation of histone gene transcription at the G1/S phase transition via the Site II cell cycle control element is distinct from E2F-dependent mechanisms operative at the growth factor-related restriction point. E2F-independent activation of histone H4 gene expression combines contributions of several promoter factors, including HiNF-M/IRF2 and the HiNF-D/CDP-cut complex which contains pRB, CDK1, and cyclin A as non-DNA binding subunits. Mutational analyses suggest additional rate-limiting factors for Site II function. Using sequence-specific Site II DNA affinity chromatography, we identified a 45 kDa protein (KIAA0005 or BZAP45) that is embryonically expressed and phylogenetically conserved. Based on amino acid sequence analysis, BZAP45 contains a unique decapeptide that is part of a putative leucine-zipper protein with a nucleotide (ATP or GTP) binding fold. Bacterial expression of a full-length cDNA produces a 45 kDa protein. Binding studies reveal that highly purified BZAP45 does not interact with Site II, suggesting that BZAP45 function may require partner proteins. Forced expression of BZAP45 strongly stimulates H4 promoter (nt -215 to -1)/CAT reporter gene activity. Deletion analyses and point mutations indicate that BZAP45 enhances H4 gene transcription through Site II. Thus, BZAP45 is a novel regulatory factor that contributes to transcriptional control at the G1/S phase transition.
    Biochemistry 10/2001; 40(35):10693-9. · 3.38 Impact Factor
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    ABSTRACT: Interferon regulatory factors (IRFs) are transcriptional mediators of interferon-responsive signaling pathways that are involved in antiviral defense, immune response, and cell growth regulation. To investigate the role of IRF proteins in the regulation of histone H4 gene transcription, we compared the transcriptional contributions of IRF-1, IRF-2, IRF-3, and IRF-7 using transient transfection assays with H4 promoter/luciferase (Luc) reporter genes. These IRF proteins up-regulate reporter gene expression but IRF-1, IRF-3, and IRF-7 are more potent activators of the H4 promoter than IRF-2. Forced expression of different IRF combinations reveals that IRF-2 reduces IRF-1 or IRF-3 dependent activation, but does not affect IRF-7 function. Thus, IRF-2 may have a dual function in histone H4 gene transcription by acting as a weak activator at low dosage and a competitive inhibitor of other strongly activating IRFs at high levels. IRF-1/IRF-3 and IRF-1/IRF-7 pairs each mediate the highest levels of site II-dependent promoter activity and can up-regulate transcription by 120-150-fold. We also find that interferon gamma up-regulates IRF-1 and site II-dependent promoter activity. This up-regulation is not observed when the IRF site is mutated or if cells are preloaded with IRF-1. Our results indicate that IRF-1, IRF-2, IRF-3, and IRF-7 can all regulate histone H4 gene expression. The pairwise utilization of distinct IRF factors provides a flexible transcriptional mechanism for integration of diverse growth-related signaling pathways.
    Journal of Biological Chemistry 06/2001; 276(21):18624-32. · 4.65 Impact Factor
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    ABSTRACT: Expression of the bone sialoprotein (BSP) gene, a marker of bone formation, is largely restricted to cells in mineralized tissues. Recent studies have shown that the Cbfa1 (also known as Runx2, AML-3, and PEBP2alphaA) transcription factor supports commitment and differentiation of progenitor cells to hypertrophic chondrocytes and osteoblasts. This study addresses the functional involvement of Cbfa sites in expression of the Gallus BSP gene. Gel mobility shift analyses with nuclear extracts from ROS 17/2.8 osteoblastic cells revealed that multiple Cbfa consensus sequences are functional Cbfa DNA binding sites. Responsiveness of the 1.2-kb Gallus BSP promoter to Cbfa factors Cbfa1, Cbfa2, and Cbfa3 was assayed in osseous and nonosseous cells. Each of the Cbfa factors mediated repression of the wild-type BSP promoter, in contrast to their well known activation of various hematopoietic and skeletal phenotypic genes. Suppression of BSP by Cbfa factors was not observed in BSP promoters in which Cbfa sites were deleted or mutated. Expression of the endogenous BSP gene in Gallus osteoblasts was similarly downregulated by forced expression of Cbfa factors. Our data indicate that Cbfa repression of the BSP promoter does not involve the transducin-like enhancer (TLE) proteins. Neither coexpression of TLE1 or TLE2 nor the absence of the TLE interaction motif of Cbfa1 (amino acids 501 to 513) influenced repressor activity. However, removal of the C terminus of Cbfa1 (amino acids 362 to 513) relieved suppression of the BSP promoter. Our results, together with the evolutionary conservation of the seven Cbfa sites in the Gallus and human BSP promoters, suggest that suppressor activity by Cbfa is of significant physiologic consequence and may contribute to spatiotemporal expression of BSP during bone development.
    Molecular and Cellular Biology 05/2001; 21(8):2891-905. · 5.37 Impact Factor
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    ABSTRACT: Interactions between Cajal bodies (CBs) and replication-dependent histone loci occur more frequently than for other mRNA-encoding genes, but such interactions are not seen with all alleles at a given time. Because CBs contain factors required for transcriptional regulation and 3' end processing of nonpolyadenylated replication-dependent histone transcripts, we investigated whether interaction with CBs is related to metabolism of these transcripts, known to vary during the cell cycle. Our experiments revealed that a locus containing a cell cycle-independent, replacement histone gene that produces polyadenylated transcripts does not preferentially associate with CBs. Furthermore, modest but significant changes in association levels of CBs with replication-dependent histone loci mimic their cell cycle modulations in transcription and 3' end processing rates. By simultaneously visualizing replication-dependent histone genes and their nuclear transcripts for the first time, we surprisingly find that the vast majority of loci producing detectable RNA foci do not contact CBs. These studies suggest some link between CB association and unusual features of replication-dependent histone gene expression. However, sustained CB contact is not a requirement for their expression, consistent with our observations of U7 snRNP distributions. The modest correlation to gene expression instead may reflect transient gene signaling or the nucleation of small CBs at gene loci.
    Molecular Biology of the Cell 04/2001; 12(3):565-76. · 4.60 Impact Factor
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    ABSTRACT: Transcriptional control at the G1/S-phase transition of the cell cycle requires functional interactions of multimeric promoter regulatory complexes that contain DNA binding proteins, transcriptional cofactors, and/or chromatin modifying enzymes. Transcriptional regulation of the human histone H4/n gene (FO108) is mediated by Interferon Regulatory Factor-2 (IRF-2), as well as other histone gene promoter factors. To identify proteins that interact with cell-cycle regulatory factors, we performed yeast two-hybrid analysis with IRF-2 and identified a novel human protein termed Celtix-1 which binds to IRF-2. Celtix-1 contains several phylogenetically conserved domains, including a bromodomain, which is found in a number of transcriptional cofactors. Using a panel of IRF-2 deletion mutants in yeast two-hybrid assays, we established that Celtix-1 contacts the C-terminus of IRF-2. Celtix-1 directly interacts with IRF-2 based on binding studies with glutathione S-transferase (GST)/IRF-2 fusion proteins, and immunofluorescence studies suggest that Celtix-1 and IRF-2 associate in situ. Celtix-1 is distributed throughout the nucleus in a heterodisperse pattern. A subset of Celtix-1 colocalizes with the hyperacetylated forms of histones H3 and H4, as well as with the hyperphosphorylated, transcriptionally active form of RNA polymerase II. We conclude that the bromodomain protein Celtix-1 is a novel IRF-2 interacting protein that associates with transcriptionally active chromatin in situ.
    Journal of Cellular Physiology 12/2000; 185(2):269-79. · 4.22 Impact Factor
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    ABSTRACT: Treatment of genetic or degenerative diseases severely affecting the entire skeleton may necessitate gene therapy involving transplantation of multipotential marrow cells. The ability of in vitro expanded adherent marrow cells enriched in pluripotent mesenchymal cell populations to remain competent to engraft, repopulate host tissues, and differentiate into bone and cartilage is advantageous for correction of skeletal-related diseases. However, to achieve phenotypic specificity and therapeutic or physiologic levels of proteins may require cell type specific expression of the gene. Tissue-specific promoter-controlled transgenes provide an efficacious approach to deliver therapeutic gene expression to repopulating chondrocytes and osteoblasts for treatment of cartilage and bone disorders or tumor metastasis to the skeleton. The bone-specific expression of a reporter gene controlled by the osteoblast-specific osteocalcin promoter after transplantation of a mixed population of marrow cells is shown. Tissue-restricted gene therapy potentially can be refined by use of a unique peptide targeting signal that directs the hematopoietic, chondrogenic, and osteogenic core binding factor/acute myelogenous leukemia transcription factors to subnuclear sites that support gene expression.
    Clinical Orthopaedics and Related Research 11/2000; · 2.79 Impact Factor
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    ABSTRACT: Contributing to bone-specific expression of the osteocalcin gene is the promoter element OC Box I (-99 to -76), which binds both Hox proteins and another nonhomeodomain factor (designated OCBP for osteocalcin-box binding protein) (Hoffmann et al. [1996] J Cell Biochem 61:310-324). OCBP correlates with increased promoter activity and may, therefore, be important to development or maintenance of the osteoblast phenotype. To identify OCBP candidates, we used a multimerized OC Box I sequence to screen a gammagt11 cDNA expression library, constructed from the rat osteosarcoma osteoblastic ROS 17/2.8 cell line, for cDNA clones encoding factors that recognize this element. Mutant OC Box I sequences that do not bind OCBP and/or homeodomain proteins were used to counterscreen the cDNA isolates. Clones showing binding specificity were sequenced and further characterized for patterns of expression in different tissues and cell lines. Among the characterized nonhomeodomain-related isolates, we identified a nucleolin, a clone encoding rCAP2 that is related to myogenic differentiation and more importantly, a cDNA clone containing a previously uncharacterized gene that has been designated as a cell differentiation-related factor (DRF). DRF mRNA is highly expressed in ROS 17/2.8 cells and in a developmentally regulated pattern during osteoblast differentiation, being upregulated at the postproliferative maturation transition and coinciding with the induction of osteocalcin gene expression. The 7.7-kb transcript encoded by clone 44 is abundantly expressed in osteoblasts, but the mRNA was not present at detectable levels in bone and soft tissues by Northern blot analysis. However, related expressed sequence tags were recently reported in cDNA libraries of rat lung and mouse sympathetic ganglion. The identification of DRF represents a novel osteoblast differentiation-specific marker related to osteocalcin expression. The identification of DRF may further facilitate definition of gene regulatory mechanisms mediating the final stages of bone cell differentiation
    Journal of Cellular Biochemistry 10/2000; 80(1):156-68. · 3.06 Impact Factor
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    ABSTRACT: The runt related transcription factor CBFA1 (AML3/PEBP2alphaA/RUNX2) regulates expression of several bone- and cartilage-related genes and is required for bone formation in vivo. The gene regulatory mechanisms that control activation and repression of CBFA1 gene transcription during osteoblast differentiation and skeletal development are essential for proper execution of the osteogenic program. We have therefore defined functional contributions of 5' regulatory sequences conserved in rat, mouse and human CBFA1 genes to transcription. Deletion analysis reveals that 0.6 kB of the bone-related rat or mouse CBFA1 promoter (P1, MASNS protein isoform) is sufficient to confer transcriptional activation, and that there are multiple promoter domains which positively and negatively regulate transcription. Progressive deletion of promoter segments between nt -351 and -92 causes a striking 30- to 100-fold combined decrease in promoter activity. Additionally, 5' UTR sequences repress reporter gene transcription 2- to 3-fold. Our data demonstrate that CBFA1 is a principal DNA binding protein interacting with the 5' region of the CBFA1 gene in osseous cells, that there are at least three CBFA1 recognition motifs in the rat CBFA1 promoter, and that there are three tandemly repeated CBFA1 sites within the 5' UTR. We find that forced expression of CBFA1 protein downregulates CBFA1 promoter activity and that a single CBFA1 site is sufficient for transcriptional autosuppression. Thus, our data indicate that the CBFA1 gene is autoregulated in part by negative feedback on its own promoter to stringently control CBFA1 gene expression and function during bone formation.
    Journal of Cellular Physiology 10/2000; 184(3):341-50. · 4.22 Impact Factor
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    ABSTRACT: Promyelocytic leukemia (PML) nuclear bodies are important components of nuclear architecture that are functionally linked to aberrant gene expression and disease. To understand the mechanisms that modify subnuclear distribution and regulatory activities of PML domains in leukemia, we performed immunofluorescence microscopy with a panel of normal diploid cells and established cell lines. We analyzed the representation and intranuclear distribution of PML domains. We find that multiple biological parameters contribute to heterogeneity in the subnuclear organization of PML domains in a broad spectrum of cell types. The subnuclear organization of PML domains was also evaluated following transient transfection with a series of vectors expressing normal hematopoietic and leukemia-related transcription factors. Our results show that expression of a chimeric transcription factor encoded by the tumor related chromosomal translocation (8;21) involving the AML1 and ETO loci is sufficient to cause reorganization of PML domains. This finding increases our understanding of the mechanisms by which the AML1/ETO protein may contribute to modified gene expression linked to the onset and progression of t(8;21) related acute myelogenous leukemia.
    Journal of Cellular Biochemistry 08/2000; 79(1):103-12. · 3.06 Impact Factor
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    ABSTRACT: The subnuclear organization of nucleic acids and cognate regulatory factors suggests that there are functional interrelationships between nuclear structure and gene expression. Nuclear proteins that are localized in discrete domains within the nucleus include the leukemia-associated acute myelogenous leukemia (AML) and promyelocytic leukemia (PML) factors, the SC-35 RNA-processing factors, nucleolar proteins and components of both transcriptional and DNA replication complexes. Mechanisms that control the spatial distribution of transcription factors within the three-dimensional context of the nucleus may involve the sorting of regulatory information, as well as contribute to the assembly and activity of sites that support gene expression. Molecular, cellular, genetic and biochemical approaches have identified distinct protein segments, termed intranuclear-targeting signals, that are responsible for directing regulatory factors to specific subnuclear sites. Gene rearrangements that remove or alter intranuclear-targeting signals are prevalent in leukemias and have been linked to altered localization of regulatory factors within the nucleus. These modifications in the intranuclear targeting of transcription factors might abrogate fidelity of gene expression in tumor cells by influencing the spatial organization and/or assembly of machineries involved in the synthesis and processing of gene transcripts.
    Journal of Cell Science 08/2000; 113 ( Pt 14):2527-33. · 5.88 Impact Factor
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    ABSTRACT: The Runt related transcription factors RUNX (AML/CBF(alpha)/PEBP2(alpha)) are key regulators of hematopoiesis and osteogenesis. Using co-transfection experiments with four natural promoters, including those of the osteocalcin (OC), multi drug resistance (MDR), Rous Sarcoma Virus long terminal repeat (LTR), and bone sialoprotein (BSP) genes, we show that each of these promoters responds differently to the forced expression of RUNX proteins. However, the three RUNX subtypes (i.e. AML1, AML2, and AML3) regulate each promoter in a similar manner. Although the OC promoter is activated in a C terminus dependent manner, the MDR, LTR and BSP promoters are repressed by three distinct mechanisms, either independent of or involving the AML C terminus, or requiring only the conserved C-terminal pentapeptide VWRPY. Using yeast two hybrid assays we find that the C terminus of AML1 interacts with a Groucho/TLE/R-esp repressor protein. Co-expression assays reveal that TLE proteins repress AML dependent activation of OC gene transcription. Western and northern blot analyses suggest that TLE expression is regulated reciprocally with the levels of OC gene expression during osteoblast differentiation. Digital immunofluorescence microscopy results show that TLE1 and TLE2 are both associated with the nuclear matrix, and that a significant subset of each colocalizes with AML transcription factors. This co-localization of TLE and AML proteins is lost upon removing the C terminus of AML family members. Our findings indicate that suppression of AML-dependent gene activation by TLE proteins involves functional interactions with the C terminus of AML at the nuclear matrix in situ. Our data are consistent with the concept that the C termini of AML proteins support activation or repression of cell-type specific genes depending on the regulatory organization of the target promoter and subnuclear localization.
    Journal of Cell Science 07/2000; 113 ( Pt 12):2221-31. · 5.88 Impact Factor
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    ABSTRACT: The transplantation of multipotential bone marrow cells containing bone tissue specific promoter-controlled transgenes provides an efficacious approach to deliver therapeutic gene expression to osteoblasts for the treatment of patients with bone disorders or tumor metastasis to the skeleton. The specificity of tissue-restricted gene therapy can be refined by utilization of a 31-amino-acid segment of the hematopoietic and osteogenic AML/CBF transcription factors that direct the regulatory proteins to subnuclear sites that support gene expression. Unfractionated adherent bone marrow cells from transgenic mice constructed with the proximal 1.7 kb of the osteocalcin gene promoter fused to a CAT reporter were transplanted by intravenous infusion. Engraftment and expression at the single-cell level within the context of tissue organization was established by immunohistochemistry using an anti-CAT antibody. Sequences that support the intranuclear trafficking of AML/CBF transcription factors to subnuclear sites that support transcription were determined by the expression and visualization of mutated and epitope tagged AML/CBF proteins. Immunohistochemical staining of an extensive series of tissue sections from mice posttransplantation using an anti-CAT antibody indicated that CAT-positive osteoblasts and osteocytes were present in bone sections. These findings indicate that donor bone marrow-derived cells engraft in bone tissue in an environment that supports maturation to the developmental stage at which a bone specific osteocalcin promoter is transcriptionally active. Characterization of functional domains in AML/CBF transcription factors has established that there are at least two regulated events that are required for targeting the factors to transcriptionally active nuclear domains: A nuclear localization signal in the amino terminal region controls nuclear import and retention, and a nuclear matrix targeting signal in the carboxyl region controls association with nuclear matrix-linked sites where transcription occurs. The specificity of hematopoietic and bone phenotypic promoters, together with the additional level of specificity inherent in the AML/CBF family of hematopoietic and osteogenic intranuclear targeting signals, offers viable options for constructing gene therapy regimens that are targeted to the skeleton for the control of metastatic disease. It is realistic to anticipate that, as additional parameters of gene regulatory mechanisms are defined, particularly components of transcriptional control that are operative within a three-dimensional context of nuclear architecture, opportunities for enhancing the effectiveness of treating patients with tumors that metastasize to bone will be extended.
    Cancer 07/2000; 88(12 Suppl):2899-902. · 5.20 Impact Factor

Publication Stats

6k Citations
1,089.66 Total Impact Points

Institutions

  • 1988–2011
    • University of Massachusetts Medical School
      • • Department of Cancer Biology
      • • Department of Cell Biology
      Worcester, MA, United States
  • 2001
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 1998
    • Wayne State University
      • Department of Anatomy and Cell Biology
      Detroit, MI, United States
  • 1997
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 1996
    • Erasmus Universiteit Rotterdam
      • Department of Internal Medicine
      Rotterdam, South Holland, Netherlands
  • 1995
    • Robert Wood Johnson University Hospital
      New Brunswick, New Jersey, United States
  • 1994
    • University of Worcester
      Worcester, England, United Kingdom
  • 1991–1994
    • University of Massachusetts Amherst
      Amherst Center, Massachusetts, United States
  • 1975–1988
    • University of Florida
      • • College of Medicine
      • • Department of Biochemistry and Molecular Biology
      Gainesville, FL, United States
  • 1985
    • Vanderbilt University
      • Department of Biochemistry
      Nashville, Michigan, United States
  • 1980
    • University of Michigan
      Ann Arbor, Michigan, United States