J L Stein

University of Vermont, Burlington, Vermont, United States

Are you J L Stein?

Claim your profile

Publications (70)381.97 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Runx1 is a transcription factor essential for definitive hematopoiesis, and genetic abnormalities in Runx1 cause leukemia. Runx1 is functionally promiscuous and acts as either an oncogene or tumor suppressor gene in certain epithelial cancers. Recent evidence suggests that Runx1 is an important factor in breast cancer, however its role remains ambiguous. Here, we addressed whether Runx1 has a specific pathological role during breast cancer progression and show that Runx1 has an oncogenic function. We observed elevated Runx1 expression in a subset of human breast cancers. Furthermore, throughout the course of disease progression in a classical mouse model of breast cancer (i.e., the MMTV-PyMT transgenic model), Runx1 expression increases in the primary site (mammary gland) and is further upregulated in tumors and distal lung metastatic lesions. Ex vivo studies using tumor epithelial cells derived from these mice express significantly higher levels of Runx1 than normal mammary epithelial cells. The tumor cells exhibit increased rates of migration and invasion, indicative of an aggressive cancer phenotype. Inhibition of Runx1 expression using RNA interference significantly abrogates these cancer-relevant phenotypic characteristics. Importantly, our data establish that Runx1 contributes to murine mammary tumor development and malignancy and potentially represents a key disease-promoting and prognostic factor in human breast cancer progression and metastasis. This article is protected by copyright. All rights reserved.
    Journal of Cellular Physiology 03/2015; 230(10). DOI:10.1002/jcp.24989 · 3.84 Impact Factor
  • RE Scott · PN Ghule · JL Stein · GS Stein ·
    [Show abstract] [Hide abstract]
    ABSTRACT: The early stages of carcinogenesis are linked to defects in the cell cycle. A series of cell cycle checkpoints are involved in this process. The G1/S checkpoint that serves to integrate the control of cell proliferation and differentiation is linked to carcinogenesis and the mitotic spindle checkpoint by its association with the development of chromosomal instability. This paper presents the outcome of systems biology studies designed to evaluate if networks of covariate cell cycle gene transcripts exist in proliferative mammalian tissues including mice, rats and humans. The GeneNetwork website that contains numerous gene expression datasets from different species, sexes and tissues represents the foundational resource for these studies (www.genenetwork.org). In addition, WebGestalt, a gene ontology tool, facilitated the identification of expression networks of genes that co-vary with key cell cycle targets, especially Cdc20 and Plk1 (www.bioinfo.vanderbilt.edu/webgestalt). Cell cycle expression networks of such covariate mRNAs exist in multiple proliferative tissues including liver, lung, pituitary, adipose and lymphoid tissues among others but not in brain or retina that have low proliferative potential. Sixty-three covariate cell cycle gene transcripts (mRNAs) compose the average cell cycle network with p = e(-13) to e(-36) . Cell cycle expression networks show species, sex and tissue variability and they are enriched in mRNA transcripts associated with mitosis many of which are associated with chromosomal instability. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Physiology 03/2015; 230(10). DOI:10.1002/jcp.24990 · 3.84 Impact Factor

  • 39th Annual Congress of the European-Calcified-Tissue-Society (ECTS); 05/2012

  • 39th Annual Congress of the European-Calcified-Tissue-Society (ECTS); 05/2012
  • [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.
    Genome Structure and Function, 07/2011: pages 57-82;

  • Bone 06/2010; 47. DOI:10.1016/j.bone.2010.04.036 · 3.97 Impact Factor

  • [Show abstract] [Hide abstract]
    ABSTRACT: Skeletal development and bone remodeling require stringent control of gene activation and suppression in response to physiological cues. This chapter focuses on contributions by several indices of nuclear architecture to the control of gene expression in bone cells. It presents cellular, biochemical, molecular, genetic, and epigenetic evidence for linkages of developmental and tissue-specific gene expression with the organization of transcriptional regulatory machinery in subnuclear compartments. The fidelity of gene regulation necessitates the coordination of transcription factor metabolism and the spatial organization of genes and regulatory proteins within the three-dimensional context of nuclear architecture. Using skeletal genes as a paradigm, this chapter addresses mechanisms that functionally organize the regulatory machinery for transcriptional activation and suppression as well as cell fate and lineage commitment during skeletal development and remodeling. It also provides evidence for consequences that result from perturbations in nuclear structure: gene expression interrelationships that are associated with skeletal disease and tumors that metastasize to bone. Finally, it suggests that there is emerging recognition that the placement of regulatory components of gene expression must be coordinated temporally and spatially to facilitate biological control. The consequences of breaches in nuclear structure-function relationships are observed in an expanding series of diseases that include cancer and neurological disorders.
  • J Pratap · J B Lian · A Javed · G L Barnes · A J van Wijnen · J L Stein · G S Stein ·
    [Show abstract] [Hide abstract]
    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. DOI:10.1007/s10555-006-9032-0 · 7.23 Impact Factor

  • Bone 03/2006; 38(3):34-34. DOI:10.1016/j.bone.2006.01.130 · 3.97 Impact Factor

  • Oncogene 01/2004; 23(24):4315-4329. · 8.46 Impact Factor

  • J B Lian · G S Stein · J L Stein · A J van Wijnen ·
    [Show abstract] [Hide abstract]
    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; · 2.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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)(12):2221-31. · 5.43 Impact Factor
  • G S Stein · A J van Wijnen · J L Stein · J B Lian · M Montecino · K Zaidi · A Javed ·
    [Show abstract] [Hide abstract]
    ABSTRACT: The regulated and regulatory components that interrelate nuclear structure and function must be experimentally established. A formidable challenge is to define further the control of transcription factor targeting to acceptor sites associated with the nuclear matrix. It will be important to determine whether acceptor proteins are associated with a pre-existing core-filament structural lattice or whether a compositely organized scaffold of regulatory factors is dynamically assembled. An inclusive model for all steps in the targeting of proteins to subnuclear sites cannot yet be proposed. However, this model must account for the apparent diversity of intranuclear targeting signals. It is also important to assess the extent to which regulatory discrimination is mediated by subnuclear domain-specific trafficking signals. Furthermore, the checkpoints that monitor subnuclear distribution of regulatory factors and the sorting steps that ensure both structural and functional fidelity of nuclear domains in which replication and expression of genes occur must be biochemically and mechanistically defined. There is emerging recognition that placement of regulatory components of gene expression must be temporally and spatially coordinated to facilitate biological control. The consequences of breaches in nuclear structure-function relationships are observed in an expanding series of diseases that include cancer [Weis et al., 1994; Rogaia et al., 1997; Yano et al., 1997; Rowley, 1998; Zeng et al., 1998; McNeil et al., 1999; Tao and Levine, 1999a] and neurological disorders [Skinner et al., 1997]. As the repertoire of architecture-associated regulatory factors and cofactors expands, workers in the field are becoming increasingly confident that nuclear organization contributes significantly to control of transcription. To gain increased appreciation for the complexities of subnuclear organization and gene regulation, we must continue to characterize mechanisms that direct regulatory proteins to specific transcription sites within the nucleus so that these proteins are in the right place at the right time. J. Cell. Biochem. Suppl. 35:84-92, 2000.
    Journal of cellular biochemistry. Supplement 02/2000; Suppl 35:84-92. DOI:10.1002/1097-4644(2000)79:35+3.3.CO;2-0
  • G S Stein · A J Van Wijnen · J L Stein · J B Lian · M Montecino · J Choi · K Zaidi · A Javed ·

  • [Show abstract] [Hide abstract]
    ABSTRACT: The bone morphogenetic protein (BMP)-2 is a potent osteoinductive signal, inducing bone formation in vivo and osteoblast differentiation from non-osseous cells in vitro. The runt domain-related protein Cbfa1/PEBP2alphaA/AML-3 is a critical component of bone formation in vivo and transcriptional regulator of osteoblast differentiation. To investigate the relationship between the extracellular BMP-2 signal, Cbfa1, and osteogenesis, we examined expression of Cbfa1 and osteoblastic genes during the BMP-2 induced osteogenic transdifferentiation of the myoblastic cell line C2C12. BMP-2 treatment completely blocked myotube formation and transiently induced expression of Cbfa1 and the bone-related homeodomain protein Msx-2 concomitant with loss of the myoblast phenotype. While induction of collagen type I and alkaline phosphatase (AP) expression coincided with Cbfa1 expression, Cbfa1 mRNA was strikingly downregulated at the onset of expression of osteopontin (OPN) and osteocalcin (OCN) genes, reflecting the mature osteoblast phenotype. TGF-beta1 treatment effectively suppressed myogenesis and induced Cbfa1 expression but was insufficient to support osteoblast differentiation reflected by the absence of ALP, OPN, and OCN. We addressed whether induction of Cbfa1 in response to BMP-2 results in the transcriptional activation of the OC promoter which contains three enhancer Cbfa1 elements. Transfection studies show BMP-2 suppresses OC promoter activity in C2C12, but not in osteoblastic ROS 17/2.8 cells. Maximal suppression of OC promoter activity in response to BMP-2 requires sequences in the proximal promoter (up to nt -365) and may occur independent of the three Cbfa sites. Taken together, our results demonstrate a dissociation of Cbfa1 expression from development of the osteoblast phenotype. Our findings suggest that Cbfal may function transiently to divert a committed myoblast to a potentially osteogenic cell. However, other factors induced by BMP-2 appear to be necessary for complete expression of the osteoblast phenotype.
    Journal of Cellular Biochemistry 05/1999; 73(1):114-25. DOI:10.1002/(SICI)1097-4644(19990401)73:13.3.CO;2-D · 3.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Evidence is accruing that the architectural organization of nucleic acids and regulatory proteins within the cell nucleus support functional interrelationships between nuclear structure and gene expression. The punctate distribution of several transcription factors has provided several paradigms for pursuing mechanisms that direct these regulatory proteins to subnuclear sites where gene activation or suppression occurs. Sequences that are necessary and sufficient to direct regulatory proteins to transcriptionally active nuclear domains have been identified. Mutations that disrupt intranuclear targeting signals lead to modified subnuclear distribution of transcription factors and aberrant expression in tumor cells. J. Cell. Biochem. Suppls. 32/33:24-31, 1999.
    Journal of Cellular Biochemistry 02/1999; Suppl 32-33:24-31. · 3.26 Impact Factor

Publication Stats

3k Citations
381.97 Total Impact Points


  • 2015
    • University of Vermont
      Burlington, Vermont, United States
  • 1994-2011
    • University of Massachusetts Medical School
      • • Department of Cancer Biology
      • • Department of Cell Biology
      Worcester, MA, United States
    • University of Worcester
      Worcester, England, United Kingdom
    • Vanderbilt University
      • Department of Biochemistry
      Нашвилл, Michigan, United States
  • 1993-1996
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, Massachusetts, United States
  • 1995
    • Wayne State University
      • Department of Anatomy and Cell Biology
      Detroit, Michigan, United States
  • 1983
    • University of Florida
      • College of Medicine
      Gainesville, Florida, United States