Begell House Inc.
Critical Reviews™ in Eukaryotic Gene Expression
CRE
1045-4403
10
2
2000
Therapeutic Angiogenesis: A Case for Targeted, Regulated Gene Delivery
14
10.1615/CritRevEukarGeneExpr.v10.i2.10
Keith A.
Webster
Department of Molecular and Cellular Pharmacology, University of Miami Medical Center, 1600 NW 10th Avenue, RMSB 6038, Miami, FL 33136
Blood and vascular disorders underlie a plethora of pathological conditions and are the single most frequent cause of human disease. Eliminated or restricted blood flow to tissues as a result of vessel dysfunction results in the disruption of oxygen and nutrient delivery and the accumulation of waste metabolites. Cells cannot survive extended severe ischemia but may be able to adapt to a moderate condition where diffusion to and from bordering nonischemic regions sustain vital functions. Under this condition, secondary functions of affected cells are likely to be impaired and a new metabolic equilibrium is established, determined by the level of cross-diffusion. In tissues with a normally high metabolic turnover such as skeletal and cardiac muscle, ischemia causes hypoxia, acidosis, and depressed function (contractility). The treatment possibilities for tissue ischemia resulting from vascular disease are limited. Lipid-lowering agents may help slow the progression of vessel disease in some instances, but surgical reconstruction may be the only option in advanced stages, and even this is not always an option. An alternative and rather obvious strategy to treat ischemia is to activate endogenous angiogenic or vasculogenic pathways and stimulate revascularization of the tissue. The feasibility of such a strategy has now been established through the results of studies over the past decade and a new discipline called therapeutic angiogenesis has emerged. This review focuses on the application of therapeutic angiogenesis for treating peripheral limb ischemia and coronary artery diseases; the author traces the evidence supporting the feasibility of this treatment strategy, its current limitations, and possible directions.
Targeting Regulatory Factors to Intranuclear Replication Sites
7
10.1615/CritRevEukarGeneExpr.v10.i2.20
Heinrich
Leonhardt
Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany
Anje
Sporbert
Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany
M. Cristina
Cardoso
Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany
Plenty of evidence exists that mammalian nuclei are highly organized. Complex biochemical processes like DNA replication take place at specialized subnuclear sites and proteins directly or indirectly involved are concentrated at these sites. DNA replication is being used as a paradigm to study this functional organization of the nucleus, its underlying principles, and its potential regulatory consequences. In this review we discuss which factors were shown to be localized at nuclear replication sites, how they get there, and what role this might play in the precise, genome-wide regulation and coordination of complex biochemical processes.
Developmental and Tissue-Specific Regulation of Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Gene Expression
16
10.1615/CritRevEukarGeneExpr.v10.i2.30
David
Goltzman
Departments of Physiology and Medicine, McGill University; and Calcium Research Laboratory, Royal Victoria Hospital and McGill University, Montreal, Canada
John H.
White
Departments of Physiology and Medicine, McGill University, Montreal, Canada
Parathyoid hormone (PTH) and PTH-related peptide (PTHrP) signal through a common PTH/PTHrP receptor (PTHR1). PTH is secreted by the parathyroids and functions in an endocrine manner to regulate extracellular fluid calcium concentrations, largely by interacting with receptors expressed in kidney and bone. PTHrP, on the other hand, is widely expressed and acts by autocrine or paracrine signaling to modulate a range of physiological and developmental responses. PTH1R1 signaling is required both in the adult and during development, and ablation of PTHR1 gene expression results in an embryonic lethal phenotype in both mice and humans. Consequently, the PTHR1 is widely expressed, and transcription of its gene is tissue specific and developmentally regulated. This review focuses on our current knowledge of the mechanisms controlling expression of the PTHR1 gene in humans and in rodents, both during development and in the adult. We also compare the conserved and distinct aspects of PTHR1 gene regulation in the two systems and their bearing on signaling by PTH and PTHrP.
Regulatory Mechanisms in Vascular Calcification
8
10.1615/CritRevEukarGeneExpr.v10.i2.40
Kristina
Bostrom
Division of Cardiology, Departments of Medicine and Physiology, UCLA School of Medicine, Los Angeles, CA 90095-1679
Linda L.
Demer
Division of Cardiology, Departments of Medicine and Physiology, UCLA School of Medicine, Los Angeles, CA 90095-1679
Vascular calcification is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality as well as a biologically regulated process potentially subject to prevention and reversal.
Both coronary and aortic calcification are common and influence plaque rupture, angioplasty and surgical complications, and compensatory enlargement. Aortic calcification increases aortic rigidity and contributes to cadiac ischemia, left ventricular hypertrophy, heart failure, and stroke. Calcification is also common in aortic valve leaflets further compounding adverse hemodynamic effects.
Vascular calcification has often been attributed to "passive" crystallization. However, functional similarities between atherosclerotic lesions and bone contradict this view and indicate that it is no more "passive" than in embryonic bone formation or bone repair. Similarities include presence of all the major components of bone osteoid, bone regulatory factors, and subpopulations of artery wall cells that retain osteoblastic lineage potential.
Several animal models for vascular calcification are available. Spontaneous vascular calcification occurs in null mice for matrix GLA protein (MGP), a small matrix protein of unknown function, and osteoprotegerin (OPG), known to modulate osteoclast differentiation. Vascular calcification may also be induced by feeding vitamin D and calcium or warfarin to normal animals, or by fat-feeding mice null for apoE or the LDL-receptor.
Overall, regulation of vascular calcification is a growing field with surprising mechanisms and connections to other fields of biology.
Molecular Mechanisms of Tumor-Bone Interactions in Osteolytic Metastases
20
10.1615/CritRevEukarGeneExpr.v10.i2.50
John M.
Chirgwin
Division of Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio; and Research Service, Veterans Administration Medical Center, San Antonio, TX 78229-3900
Theresa A.
Guise
Division of Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900
In patients with advanced disease, several cancer types frequently metastasize to the skeleton, where they cause bone destruction. Osteolytic metastases are incurable and cause pain, hypercalcemia, fracture, and nerve compression syndromes. It was proposed over a century ago that certain cancers, such as that of the breast, preferentially metastasize to the favorable microenvironment provided by bone. Bone matrix is a rich store of immobilized growth factors that are released during bone resorption. Histological analysis of osteolytic bone metastases indicates that the bone destruction is mediated by the osteoclast rather than directly by the tumor cells. These observations suggest a vicious cycle driving the formation of osteolytic metastases: tumor cells secrete factors stimulating osteoclasts through adjacent bone marrow stromal cells; osteoclastic resorption in turn releases growth factors from the bone matrix; finally, locally released growth factors activate the tumor cells. This vicious cycle model has now been confirmed at the molecular level. In particular, transforming growth factor β (TGFβ) is abundant in bone matrix and released as a consequence of osteoclastic bone resorption. Bone-derived TGFβ plays an integral role in promoting the development and progression of osteolytic bone metastases by inducing tumor production of parathyroid hormone-related protein (PTHrP), a known stimulator of osteoclastic bone resorption. In breast cancer cells TGFβ appears to stimulate PTHrP secretion by a posttranscriptional mechanism through both Smad and p38 mitogen activated protein (MAP) kinase signaling pathways. Osteolytic metastases can be suppressed in vivo by inhibition of bone resorption, blockade of TGFβ signaling in tumor cells, and by neutralization of PTHrP. Other factors released from bone matrix may also act on tumor cells in bone, which in turn may produce other factors that stimulate bone resorption, following the vicious cycle paradigm established for TGFβ and PTHrP. An understanding at the molecular level of the mechanisms of osteolytic metastasis will result in more effective therapies for this devastating complication of cancer.
Chromosome Territories, Interchromatin Domain Compartment, and Nuclear Matrix: An Integrated View of the Functional Nuclear Architecture
38
10.1615/CritRevEukarGeneExpr.v10.i2.60
T.
Cremer
Institute of Anthropology and Human Genetics, Ludwig Maximilians University, Richard Wagner Str. 10, D-80333 Munich; and Interdisciplinary Center for Scientific Computing, Ruprecht Karls University, D-69120 Heidelberg, Germany
G.
Kreth
Interdisciplinary Center for Scientific Computing (Graduate College), Ruprecht Karls University; Applied Optics and Information Processing, Kirchhoff-lnstitute of Physics, Ruprecht Karls University, Albert-Ueberle-Str. 3-5, D-69120, Heidelberg, Germany
H.
Koester
Max-Planck-Institute for Biomedical Research, D-69120 Heidelberg, Germany
R. H. A.
Fink
Physiological Institute, Ruprecht Karls University, D-69120 Heidelberg, Germany
R.
Heintzmann
Applied Optics and Information Processing, Kirchhoff-lnstitute of Physics, Ruprecht Karls University, Albert-Ueberle-Str. 3-5, D-69120 Heidelberg, Germany
M.
Cremer
Institute of Anthropology and Human Genetics, Ludwig Maximilians University, Richard Wagner Str. 10, D-80333 Munich, Germany
I.
Solovei
Institute of Anthropology and Human Genetics, Ludwig Maximilians University, Richard Wagner Str. 10, D-80333 Munich, Germany
D.
Zink
Institute of Anthropology and Human Genetics, Ludwig Maximilians University, Richard Wagner Str. 10, D-80333 Munich, Germany
C.
Cremer
Interdisciplinary Center for Scientific Computing, Ruprecht Karls University; Applied Optics and Information Processing, Kirchhoff-lnstitute of Physics, Ruprecht Karls University, Albert-Ueberle-Str. 3-5, D-69120 Heidelberg, Germany
Advances in the specific fluorescent labeling of chromatin in fixed and living human cells in combination with three-dimensional (3D) and 4D (space plus time) fluorescence microscopy and image analysis have opened the way for detailed studies of the dynamic, higher-order architecture of chromatin in the human cell nucleus and its potential role in gene regulation. Several features of this architecture are now well established:
Chromosomes occupy distinct territories in the cell nucleus with preferred nuclear locations, although there is no evidence of a rigid suprachromosomal order.
Chromosome territories (CTs) in turn contain distinct chromosome arm domains and smaller chromatin foci
or domains with diameters of some 300 to 800 nm and a DNA content in the order of 1 Mbp.
Gene-dense, early-replicating and gene-poor, middle-to-late-replicating chromatin domains exhibit different higher-order nuclear patterns that persist through all stages of interphase. In mitotic chromosomes early replicating chromatin domains give rise to Giemsa light bands, whereas middle-to-late-replicating domains form Giemsa dark bands and C-bands.
In an attempt to integrate these experimental data into a unified view of the functional nuclear architecture, we present a model of a modular and dynamic chromosome territory (CT) organization. We propose that basically three nuclear compartments exist, an "open" higher-order chromatin compartment with chromatin domains containing active genes, a "closed" chromatin compartment comprising inactive genes, and an interchromatin domain (ICD) compartment (Cremer et al., 1993; Zirbel et al., 1993) that contains macromolecular complexes for transcription, splicing, DNA replication, and repair. Genes in "open," but not in "closed" higher-order chromatin compartments have access to transcription and splicing complexes located in the ICD compartment. Chromatin domains that build the "open" chromatin compartment are organized in a way that allows the direct contact of genes and nascent RNA to transcription and splicing complexes, respectively, preformed in the ICD compartment. In contrast, chromatin domains that belong to the "closed" compartment are topologically arranged and compacted in a way that precludes the accessibility of genes to transcription complexes. We argue that the content of the ICD compartment is highly enriched in DNA depleted biochemical matrix preparations. The ICD compartment may be considered as the structural and functional equivalent of the in vivo nuclear matrix. A matrix in this functional sense is compatible with but does not necessitate the concept of a 3D nuclear skeleton existing of long, extensively arborized filaments. In the absence of unequivocal evidence for such a structural matrix in the nucleus of living cells we keep an agnostic attitude about its existence and possible properties in maintaining the higher-order nuclear architecture. Quantitative modeling of the 3D and 4D human genome architecture in situ shows that such an assumption is not necessary to explain presently known aspects of the higher-order nuclear architecture. We expect that the interplay of quantitative modeling and experimental tests will result in a better understanding of the compartmentalized nuclear architecture and its functional consequences.