Lina Zhang

Dartmouth Medical School, Hanover, NH, United States

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Publications (6)15.78 Total impact

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    ABSTRACT: Core-binding factors (CBFs) are a small family of heterodimeric transcription factors that play critical roles in several developmental pathways and in human disease. Mutations in CBF genes are found in leukemias, bone disorders, and gastric cancers. CBFs consist of a DNA-binding CBF alpha subunit (Runx1, Runx2, or Runx3) and a non-DNA-binding CBF beta subunit. CBF alpha binds DNA in a sequence-specific manner, whereas CBF beta enhances DNA binding by CBF alpha. Both DNA binding and heterodimerization with CBF beta are mediated by a single domain in the CBF alpha subunits known as the "Runt domain." We analyzed the energetic contribution of amino acids in the Runx1 Runt domain to heterodimerization with CBF beta. We identified two energetic "hot spots" that were also found in a similar analysis of CBF beta (Tang, Y.-Y., Shi, J., Zhang, L., Davis, A., Bravo, J., Warren, A. J., Speck, N. A., and Bushweller, J. H. (2000) J. Biol. Chem. 275, 39579-39588). The importance of the hot spot residues for Runx1 function was demonstrated in in vivo transient transfection assays. These data refine the structural analyses and further our understanding of the Runx1-CBF beta interface.
    Journal of Biological Chemistry 09/2003; 278(35):33097-104. · 4.65 Impact Factor
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    ABSTRACT: The requirement of Runx2 (Cbfal/AML3), a runt homology domain transcription factor essential for bone formation and osteoblast differentiation, is well established. Although Runx2 is expressed in the developing embryo prior to ossification, yet in the absence of Runx2 initial formation of the skeleton is normal, suggesting a potential redundancy in function of Runx family members. Here we addressed expression of the hematopoietic family member Runx1 (AML1/Cbfa2) in relation to skeletal development using a LacZ knock-in mouse model (Runx1(lz/+)). The resulting fusion protein reflects Runx1 promoter activity in its native context. Our studies show that Runx1 is expressed by prechondrocytic tissue forming the cartilaginous anlagen in the embryo, resting zone chondrocytes, suture lines of the calvarium, and in periosteal and perichondral membranes of all bone. Runx1 continues to be expressed in these tissues in adult mice, but is absent in mature cartilage or mineralized bone. However, hyaline cartilage outside the bone environment (trachea, xiphoid tissues), and epithelium of many soft tissues (trachea, thyroid, lung, skin) also express Runx1. The robust expression of Runx1 in vivo in chondroblasts at sites of cartilage growth and in osteoblasts at sites of new bone formation, suggests that Runx1 expression may be related to osteochondroprogenitor cell differentiation. This observation is further supported by high expression of Runx1 in ex vivo cultures of marrow stromal cells and calvarial derived osteoblasts from Runx1(lz/+) mice. These data indicate that Runx1 may contribute to the early stages of skeletogenesis and continues to function in the progenitor cells of tissues that support bone formation in the adult.
    Journal of Cellular Physiology 09/2003; 196(2):301-11. · 4.22 Impact Factor
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    ABSTRACT: Core binding factors (CBFs) are heterodimeric transcription factors consisting of a DNA-binding CBFα subunit and non-DNA-binding CBFβ subunit. DNA binding and heterodimerization is mediated by a single domain in the CBFα subunit called the Runt domain, while sequences flanking the Runt domain confer other biochemical activities such as transactivation. On the other hand, the heterodimerization domain in CBFβ is the only functional domain that has been identified in this subunit. The biophysical properties of the Runt domain and the CBFβ heterodimerization domain, and the structures of the isolated domains as well as of the Runt domain-DNA, Runt domain-CBFβ, and ternary Runt domain-CBFβ-DNA complexes, have been characterized over the past several years, and are summarized in this review.
    Blood Cells Molecules and Diseases - BLOOD CELLS MOLECULES DIS. 01/2003; 30(2):147-156.
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    ABSTRACT: Chromosomal translocations involving the human CBFB gene, which codes for the non-DNA binding subunit of CBF (CBF beta), are associated with a large percentage of human leukemias. The translocation inv(16) that disrupts the CBFB gene produces a chimeric protein composed of the heterodimerization domain of CBF beta fused to the C-terminal coiled-coil domain from smooth muscle myosin heavy chain (CBF beta-SMMHC). Isothermal titration calorimetry results show that this fusion protein binds the Runt domain from Runx1 (CBF alpha) with higher affinity than the native CBF beta protein. NMR studies identify interactions in the CBF beta portion of the molecule, as well as the SMMHC coiled-coil domain. This higher affinity provides an explanation for the dominant negative phenotype associated with a knock-in of the CBFB-MYH11 gene and also helps to provide a rationale for the leukemia-associated dysregulation of hematopoietic development that this protein causes.
    Nature Structural Biology 10/2002; 9(9):674-9.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Core-binding factors (CBFs) are a small family of heterodimeric transcription factors that play critical roles in several developmental pathways, including hematopoiesis and bone development. Mutations in CBF genes are found in leukemias and bone disorders. CBFs consist of a DNA-binding CBFα subunit (Runx1, Runx2, or Runx3) and a non-DNA-binding CBFβ subunit. CBFα binds DNA in a sequence-specific manner, whereas CBFβ enhances DNA binding by CBFα. Recent structural analyses of the DNA-binding Runt domain of CBFα and the CBFβ subunit identified the heterodimerization surfaces on each subunit. Here we identify amino acids in CBFβ that mediate binding to CBFα. We determine the energy contributed by each of these amino acids to heterodimerization and the importance of these residues forin vivo function. These data refine the structural analyses and further support the hypothesis that CBFβ enhances DNA binding by inducing a conformational change in the Runt domain.
    Journal of Biological Chemistry 12/2000; 275(50):39579-39588. · 4.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Core binding factors (CBFs) are heterodimeric transcription factors consisting of a DNA-binding CBF alpha subunit and non-DNA-binding CBF beta subunit. DNA binding and heterodimerization is mediated by a single domain in the CBF alpha subunit called the Runt domain, while sequences flanking the Runt domain confer other biochemical activities such as transactivation. On the other hand, the heterodimerization domain in CBF beta is the only functional domain that has been identified in this subunit. The biophysical properties of the Runt domain and the CBF beta heterodimerization domain, and the structures of the isolated domains as well as of the Runt domain-DNA, Runt domain-CBF beta, and ternary Runt domain-CBF beta-DNA complexes, have been characterized over the past several years, and are summarized in this review.
    Blood Cells Molecules and Diseases 30(2):147-56. · 2.26 Impact Factor

Publication Stats

93 Citations
15.78 Total Impact Points

Institutions

  • 2000–2003
    • Dartmouth Medical School
      • Department of Biochemistry
      Hanover, NH, United States
  • 2002
    • University of Virginia
      • Department of Molecular Physiology and Biological Physics
      Charlottesville, VA, United States