Begell House Inc.
Critical Reviews™ in Eukaryotic Gene Expression
CRE
1045-4403
15
3
2005
Point Mutations in the AML1/RUNX1 Gene Associated with Myelodysplastic Syndrome
183-196
10.1615/CritRevEukarGeneExpr.v15.i3.10
Hironori
Harada
Department of Hematology/Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
Yuka
Harada
International Radiation Information Center, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells characterized by ineffective and inadequate hematopoiesis. Because MDS is a heterogeneous disorder, specific gene abnormalities implicated in the pathogenesis of MDS have been difficult to identify. Cytogenetic abnormalities are seen in half of the MDS patients and generally consist of partial or complete chromosome deletion or addition, whereas balanced translocations are rare. Although point mutations of critical genes had been demonstrated to contribute to the development of MDS, there was no strong correlation between these mutations and clinical features. Recently, we reported the high incidence of somatic mutations in the AML1/RUNX1 gene (which is a critical regulator of definitive hematopoiesis and the most frequent target for translocation of acute myeloid leukemia [AML]) in MDS, especially refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEBt), and AML following MDS (defined here as MDS/AML). The MDS/AML patients with AML1 mutations had a significantly worse prognosis than those without AML1 mutations. Most AML1 mutants lose trans-activation potential, which leads to a loss of AML1 function. These data indicate that AML1 point mutation is one of the major causes of MDS/AML, and "MDS/AML with AML1 mutation" represents a distinct clinicopathologic-genetic entity.
Biological Implications of Filamin A-Bound PEBP2β/CBFβ Retention in the Cytoplasm
197-206
10.1615/CritRevEukarGeneExpr.v15.i3.20
Toshio
Watanabe
Department of Molecular Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan
Naomi
Yoshida
Department of Molecular Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan
Masanobu
Satake
Department of Molecular Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan
Multiple mechanisms regulate dynamic cytoplasmic-to-nuclear transport of transcription factors. However, little is known about the involvement of cytoskeletal proteins in this process. The heterodimeric transcription factor PEBP2/CBF is composed of a DNA-binding subunit, Runx1, and a non-DNA-binding subunit, PEBP2β/CBFβ. The Runx1 protein possesses nuclear localization signals and is found exclusively in the nucleus, whereas PEBP2β is located in the cytoplasm in most cells and tissues examined thus far. We investigated the mechanism by which PEBP2β localizes to the cytoplasm and found that it associates with filamin A, an actin-binding cytoskeletal protein. Filamin A retains PEBP2β in the cytoplasm, thereby hindering its engagement as a Runx1 partner. When filamin A is absent, PEBP2β moves into the nucleus and enhances Runx1-dependent transcription. These observations highlight the significance of the subcellular localization of PEBP2β in regulating its activity as a component of the PEBP2/CBF transcription factor. In humans, PEBP2β is frequently targeted in the leukemia-associated chromosomal abnormality, inversion 16 (inv 16). Thus, identifying the factors that mediate the subcellular localization of the PEBP2β-derived chimeric transcription factor produced by inv 16 is an important issue that will need to be resolved in order to understand the mechanism(s) involved in inv 16-induced leukemogenesis.
AML1-ETO—Mediated Erythroid Inhibition: New Paradigms for Differentiation Blockade by a Leukemic Fusion Protein
207-216
10.1615/CritRevEukarGeneExpr.v15.i3.30
Youngjin
Choi
Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908
Kamaleldin E.
Elagib
Department of Pathology, University of Virginia School of Medicine, PO Box 800904, Charlottesville, VA 22908
Adam N.
Goldfarb
Department of Pathology, University of Virginia School of Medicine, PO Box 800904, Charlottesville, VA 22908
The chromosomal translocation t(8;21), generating the AML1-ETO fusion protein, is frequently associated with French-American-British (FAB) type M2 acute myeloid leukemia (AML). t(8;21) fuses the runt domain from the hematopoietic transcription factor RUNX1 with almost the entire transcriptional repressor ETO. AML1-ETO inhibits normal definitive hematopoiesis and blocks erythroid differentiation. Several mechanistic models for the role of AML1-ETO in leukemia development have emerged over the last decade. Most of these models have emphasized the capacity of the fusion protein to redirect repressive cofactors, such as histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), to RUNX target genes, thereby reversing the hematopoietic transcriptional program activated by wild-type RUNX1—a phenomenon referred to collectively in this review as the "classical" corepressor model. Because erythropoiesis occurs in a RUNX-independent manner, this dominant-negative "classical" model cannot explain the prominent repression of red-cell development by AML1-ETO. This review will consider the clinical and mechanistic significance of erythroid inhibition by AML1-ETO. Additional models to account for this mysterious oncogenic function are proposed.
Increased Dosage of the RUNX1/AML1 Gene: A Third Mode of RUNX Leukemia?
217-228
10.1615/CritRevEukarGeneExpr.v15.i3.40
Motomi
Osato
Institute of Molecular and Cell Biology, Oncology Research Institute, National University of Singapore, 138673 Singapore
Yoshiaki
Ito
Oncology Research Institute,
Blk MD 11, Clinical Research Centre,
10 Medical Drive, Level 5, 117597
Singapore
RUNX1/AML1, located on chromosome 21, is a key factor in the generation and maintenance of hematopoietic stem cells and the gene most frequently implicated in human leukemias. Chromosome translocations and point mutations are well-documented genetic alterations in RUNX leukemia (also known as CBF leukemia). In addition, overdosage or overexpression of RUNX1 is suspected to be a third mode of RUNX1 involvement in leukemogenesis. The possibility that this mode might underlie Down syndrome-related leukemias caused by trisomy of chromosome 21 is discussed.
Parameters of LRP5 from a Structural and Molecular Perspective
229-242
10.1615/CritRevEukarGeneExpr.v15.i3.50
Mark L.
Johnson
Creighton University School of Medicine, Osteoporosis Research Center, 601 North 30th Street, Suite 6730, Omaha, NE 68131; current address: Department of Oral Biology, UMKC School of Dentistry, 650 East 25th Street, Kansas City, MO 64108
Douglas T.
Summerfield
Creighton University School of Medicine, Osteoporosis Research Center, 601 North 30th Street, Suite 6730, Omaha, NE 68131
LRP5, along with LRP6 and their Drosophila homolog, Arrow, constitute a novel subclass of the LDL receptor superfamily. The arrangement of structural motifs in these receptors is different from the other members of the superfamily, and only recently have we begun to understand the functional importance of human LRP5 (and LRP6). Whole genome positional cloning studies have identified a number of mutations in LRP5 that underlie inherited human diseases/phenotypes, particularly those involving the skeleton and the eye. A number of studies have illustrated the importance of Lrp5/6/Arrow as a co-receptor with Frizzled for the Wnt proteins and their critical role in the regulation of the Wnt/β-catenin signaling pathway. The cataloging of these human mutations, in combination with engineered mutations in mice and other studies involving gene/protein modifications, has led to a better understanding of the function of the various domains in LRP5/6. In this review, we discuss a number of studies that have revealed a wide variety of protein-protein interactions that occur with the various structural motifs in the Lrp5 protein. Ultimately, these interactions regulate the activity of the Wnt/β-catenin signaling pathway and the role it plays in processes such as bone mass accrual and vision.
Role of Runx Proteins in Chondrogenesis
243-254
10.1615/CritRevEukarGeneExpr.v15.i3.60
Carolina A.
Yoshida
Div.of Oral Cytology/Cell Biology,Dept.of Developmental/Reconstructive Medicine,Nagasaki University Graduate School of Biomedical Sciences,Nagasaki;and Dept.of Orthodontics/Dentofacial Orthopedics,Osaka University Graduate School of Dentistry,Osaka,Japan
Toshihisa
Komori
Division of Oral Cytology and Cell Biology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1 -7-1 Sakamoto, Nagasaki, Nagasaki 852-8588, Japan
The mammalian RUNX protein family comprises three transcription factors—RUNX1, RUNX2, and RUNX3. RUNX1 is involved in hematopoiesis, RUNX2 has multiple roles in osteogenesis and RUNX3 is associated with neural and gut development. In addition, all RUNX proteins are expressed during chondrogenesis, the process by which cartilage is formed. This review describes the involvement of Runx proteins in chondrogenesis, delineating their expression pattern and emphasizing their active roles in mesenchymal condensation, chondrocyte proliferation, and chondrocyte maturation. It also highlights how Runx proteins regulate transcription of target genes and how Runx proteins are regulated in the cartilaginous skeleton.
Signal Transduction and Actin in the Regulation of G1-Phase Progression
255-276
10.1615/CritRevEukarGeneExpr.v15.i3.70
Maarten J. A.
Moes
Department of Cell Architecture and Dynamics, Institute of Biomembranes, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands
Johannes
Boonstra
Department of Cell Architecture and Dynamics, Institute of Biomembranes, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands
Regulation of cell proliferation is dependent on the integration of signal transduction systems that are activated by external signal molecules, such as growth factors and extracellular matrix components. Dependent on these signal transduction networks, the cells decide in the G1 phase to continue proliferation or, alternatively, to stop cell-cycle progression and undergo apoptosis, differentiation, or quiescence. The MAP kinase and PI-3 kinase pathways have been demonstrated to play an essential role in these G1-phase decisions. Interestingly, actin has been demonstrated to mutually interfere with signal transduction. In addition, it has been indicated that the FOXO transcription factors are involved in these decisions, as well. Actin has been demonstrated to play an important role in the regulation of G1-phase progression. Because of its properties as a structural protein, actin is essential in cytokinesis and in cell spreading and, thus, is involved in G1-phase progression. As an intermediate factor in signal transduction, actin is likely to be involved in cell-cycle regulation induced by external signal molecules. And, finally, actin has been demonstrated to play a direct role in transcription. These observations indicate a prominent role of actin in the regulation of G1-phase progression.