Begell House Inc.
Critical Reviews™ in Eukaryotic Gene Expression
CRE
1045-4403
5
3-4
1995
The Role of Cytokines and Growth Factors as Mediators of the Effects of Systemic Hormones at the Bone Local Level
193-217
10.1615/CritRevEukarGeneExpr.v5.i3-4.10
Jose A.
Riancho
Department of Internal Medicine, Hospital M. Valdecilla, University of Cantabria, Santander, Spain
Gregory R.
Mundy
Division of Endocrinology, Department of Medicine, University of Texas Health Science Center, San Antonio, TX
interleukins
osteoblasts
osteoclasts
estrogen
parathyroid hormone
vitamin D
glucocorticoids
calcitonin
growth hormone.
Bone tissue is being continuously remodeled by the integrated activity of bone-resorbing osteoclasts and bone-forming osteoblasts. Because bone remodeling takes place in discrete foci throughout the skeleton, local mechanisms must play a critical role in its regulation. Several cytokines and other locally released factors exert marked effects on bone cells. Many experimental studies show that calciotropic hormones modulate cytokine expression. Indeed, a number of studies suggest that cytokines are actually involved in the mechanisms that mediate the effects of calciotropic hormones at the areas of bone being remodeled. However, the results are often conflicting. Moreover, most published studies have been carried out by testing the effects of pharmacological concentrations of hormones on cytokine production by bone cells. This type of study often gives little information on the physiological role of the factors tested. Thus, although evidence for a role of cytokines as mediators of hormone effects at the bone local level is rapidly accumulating, more data are needed in order to better understand the actual role of those factors in bone physiology and pathophysiology. In vivo studies and particularly those analyzing the consequences of the lack of activity of a particular cytokine or hormone are likely to be particularly informative.
Regulation and Regulatory Role of the Retinoids
219-253
10.1615/CritRevEukarGeneExpr.v5.i3-4.20
Kong Wan
Ng
Department of Medicine, The University of Melbourne, St Vincent's Hospital, Fitzroy 3065, Australia
Hong
Zhou
Department of Medicine, The University of Melbourne, St Vincent's Hospital, Fitzroy 3065, Australia
Shehnaaz
Manji
Department of Medicine, The University of Melbourne, St Vincent's Hospital, Fitzroy 3065, Australia
T. John
Martin
St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, Fitzroy, 3065, Victoria, Australia
posttranscriptional action
limb bud formation
morphogenesis.
Retinoids regulate differentiation and cellular growth, exerting their physiological action by interacting with two families of nuclear receptors, the retinoic acid receptors (RARs), and the retinoid X receptors (RXRs), which regulate gene expression by forming transcriptionally active heterodimeric RAR/RXR or homodimeric RXR/RXR complexes on DNA. Although RAR/RXR heterodimers form preferentially in vitro and in vivo, it does not exclude the possibility that RXR/RXR homodimers may regulate a distinct signaling pathway. Synthetic retinoids that selectively activate or antagonize retinoic acid receptor isoforms promises to be useful tools for the elucidation of specific retinoid response pathways. Considerable progress has been made in understanding the molecular basis underlying limb bud formation, particularly the manner in which retinoic acid interacts with other signaling molecules to determine pattern formation. The phenotypic abnormalities observed in compound null mutants of retinoid receptors, recapitulating those described in the vitamin A deficiency syndrome, confirm the crucial function of endogenous retinoids in fetal development. However, the absence of phenotypic abnormalities in null mutants of individual RAR isoforms raises the possibility of functional redundancy among RAR subtypes and at the same time challenging the concept that the diverse effects of retinoids are related to the multiplicity of functionally distinct receptors.
Lessons in Transcriptional Regulation Learned from Studies on Immunoglobulin Genes
255-280
10.1615/CritRevEukarGeneExpr.v5.i3-4.30
Andrew J.
Henderson
Department of Microbiology, Columbia University College of Physicians and Surgeons, New York
Kathryn L.
Calame
Department of Microbiology, Columbia University College of Physicians and Surgeons, New York
immunoglobulin heavy chain
immunoglobulin kappa chain
transcription
enhancer
chromatin
tissue-specificity.
In this article, we consider basic principles of eukaryotic gene transcriptional regulation which have emerged from studies on immunoglobulin heavy chain and kappa chain genes. Four areas are considered: (1) regulation by distant enhancer elements, (2) multiple regulators in a given element including particular families of regulators which were discovered by studying Ig genes, (3) achieving tissue specificity of transcription by multiple mechanisms and (4) the importance of chromatin structure for transcriptional regulation.
The Phylogeny of Alpha-Fetoprotein in Vertebrates: Survey of Biochemical and Physiological Data
281-316
10.1615/CritRevEukarGeneExpr.v5.i3-4.40
G.J.
Mizejewski
Wadsworth Center, New York State Department of Health, P.O. Box 509, Room E-571, Albany, NY 12201-0509
ALB = albumin; AFP = alpha-fetoprotein; ALB molecules are represented by 64 to 69 kDa forms; ALB-like AFP molecules are represented by 70 to 74 kDa forms
and
The phylogeny of vertebrate alpha-fetoprotein (AFP) was surveyed in the phylum Chordata, including subphyla, agnatha, and Gnathostoma. A molecular taxonomic approach was undertaken based on biochemical, endocrinological, immunological, and physiological criteria previously documented for AFP. These published data were then discussed in light of their position and relationship in the albuminoid gene superfamily derived from GenBank. The phylogeny of the AFP molecule should prove useful for investigators seeking markers for animal models of human diseases, serological cross-reactivity between AFP molecular species, identification of larval or fetal protein homologs of AFP, and provide strategies for biochemical purification and physiological studies. The phylogeny of AFP in vertebrates was surveyed from the cyclostomata (lamphrey) to the mammals, including sharks, bony fishes, amphibians, reptiles, and birds. A trend was denoted, from lower to higher animal forms, in a size reduction and separation of AFP-like albumin molecular moieties from forms that resembled true albumin molecules. While the primitive lamphrey possesses a serum protein twice the size of mammalian albumin, the bony fishes, reptiles, and amphibians display two ALB-like molecules sharing amino acid sequence similarity to mammalian AFP. However, only one of the ALB-like molecules in the fish and amphibia is glycosylated. Although little has been published on reptilian AFP-like molecules, avian AFP has been investigated extensively following its detection and isolation for developmental studies involving immunology and neuroendocrinology. Finally, a plethora of knowledge exists in mammals following several decades of studies involving the isolation, purification, and characterization of AFP for use in physiological, immunological, and endocrinological research endeavors. In overview, a tendency or trend in down-sizing of an AFP-like albumin molecule and the separation of true albumin forms from a distinct fetal glycosylated form was observed. This seemed to occur in animal classes lacking a free-swimming larval form and possessing either highly differentiated extra-embryonic membranes or displaying a placenta intimately interfaced with the maternal tissues of the uterus.
Transcriptional Control Mechanisms in the Regulation of Cholesterol Balance
317-335
10.1615/CritRevEukarGeneExpr.v5.i3-4.50
Timothy F.
Osborne
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92717-3900
sterol regulatory element
SREBP-1 and -2
LDL receptor
HMG CoA synthase and reductase.
The mechanisms that govern regulation of cholesterol metabolism in higher eukaryotic cells provide an example of how metabolic regulation has evolved to establish growth and nutritional control in a multicellular environment. Two sources of cholesterol must be balanced to ensure optimum growth and viability. Much of the control is established by regulating the levels of key proteins involved in cholesterol uptake and biosynthesis and this occurs by alterations in promoter activity. The studies discussed here track the progression in understanding the mechanism for transcriptional regulation by cholesterol from the isolation of the key genes involved, to the careful dissection of the cis-acting sequences that control expression, and on to what is currently known about the trans-acting proteins that mediate the regulatory response.
A New Transcription Factor Family Associated with Human Leukemias
337-364
10.1615/CritRevEukarGeneExpr.v5.i3-4.60
Nancy A.
Speck
Abramson Family Cancer Research Institute and Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Terryl
Stacy
Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755
CBF
PEBP2
AML1
CBFB
t(8;21)
t(3;21)
t(12;21)
inv(16).
The proteins known as the polyoma enhancer binding protein 2 or core-binding factor (PEBP2/CBF) are heterodimeric transcription factors that contain a DNA-binding subunit (CBFα), and a subunit that does not bind DNA independently (CBFβ). PEBP2 and CBF were identified independently as proteins that regulate transcription of viral and cellular enhancers, and also as proteins whose genes are disrupted by chromosomal abnormalities in human leukemias. This review traces the history of the discovery of the PEBP2 and CBF protein family and describes the biochemical properties of the normal and oncogenic forms of these proteins.
Indirect and Direct Disruption of Transcriptional Regulation in Cancer: E2F and AML-1
365-383
10.1615/CritRevEukarGeneExpr.v5.i3-4.70
Shari
Meyers
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105
Scott W.
Hiebert
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105
AML-l
E2F
DP-1
t(8;21)
t(12;21)
translocation
The disruption of transcriptional regulatory circuits through the elimination of negative regulatory factors (tumor suppressors), the activation of positive acting factors (oncogenes), or when chimeric proteins result from chromosomal translocations, is likely a key event in multistep tumorigenesis. Here, using the transcription factors E2F and AML-1 as model systems, we discuss the disruption of coordinate transcriptional regulation in oncogenesis. E2F oncogenic signals are released when the pRb tumor suppressor is inactivated, and E2F activation may necessitate the coordinate inactivation of a second tumor suppressor, p53. AML-1 is the target of the (8;21) translocation, found in approximately 15% of acute myeloid leukemia (AML) cases, and the t(12;21), found in up to 30% of childhood B-cell acute lymphoblastic leukemias. The t(8;21) creates a fusion protein between AML-1 and a gene of unknown function, mtg8 (ETO), whereas the t(12:21) fuses the TEL (translocation-ets-leukemia) transcription factor to the N-terminus of AML-1. The inv(16), which is the most frequent anomaly found in AML, also targets AML-1, by fusing the gene that encodes AML-l's heterodimeric partner CBFβ to the smooth muscle myosin heavy chain gene MYH11. Thus, E2F and AML-1 provide excellent models for the disruption of transcriptional regulation in cancer.
Regulation and Regulatory Role of Proteinase Inhibitors
385-436
10.1615/CritRevEukarGeneExpr.v5.i3-4.80
R. Michael
Roberts
Departments of Animal Sciences and Biochemistry, University of Missouri, 158 Animal Science Research Center, Columbia, MO 65211
Nagappan
Mathialagan
Departments of Animal Sciences University of Missouri, 158 Animal Science Research Center, Columbia, MO 65211
Jodie Y.
Duffy
Departments of Animal Sciences,University of Missouri ,158 Animal Science Research Center, Columbia, MO 65211
George W.
Smith
Departments of Animal Sciences, University of Missouri, 158 Animal Science Research Center, Columbia, MO 65211
Gene expression: promoter
regulatory element
transcription factor
acute phase response
interleukin-6; Pathology: emphysema
Alzheimer's disease
arthritis
clotting
coagulation
complement
fibrinolysis
metastasis
inflammation; Protein structure: X-ray crystallography
Excess or ill-timed proteolytic events have, of necessity, to be restrained. Therefore, there are partner proteinase inhibitors to most of the known mammalian enzymes that cleave peptide bonds, a situation that implicates the inhibitors in a myriad of normal as well as pathological processes. Here, what is currently known about the regulatory functions, the mode of action, and the control of gene expression of the commoner extracel-lularly acting proteinase inhibitors is reviewed. The review covers four families of serine proteinase inhibitors: the serpins, the Kunitz, Kazal, and leukoproteinase inhibitors, which overlap considerably in the range of their specificities but differ considerably in their respective structures and likely functions. There then follows a description of the growing family of metalloproteinase inhibitors (usually known by the acronym TIMP), the structurally varied cysteine proteinase inhibitors, and finally α2-macroglobulin, a large multisubunit inhibitor, that is relatively catholic in its range of targets. The review concludes with two short sections, the first an overview of the acute phase response, which features several proteinase inhibitors from the different families discussed earlier, and the second, our prediction of where this research field is headed over the next decade.
SUBJECT INDEX
437-438
10.1615/CritRevEukarGeneExpr.v5.i3-4.90
AUTHOR INDEX
439
10.1615/CritRevEukarGeneExpr.v5.i3-4.100