Begell House Inc.
Critical Reviews™ in Eukaryotic Gene Expression
CRE
1045-4403
15
1
2005
Osteoclastogenesis: The Role of Calcium and Calmodulin
1-13
10.1615/CritRevEukaryotGeneExpr.v15.i1.10
Liang
Zhang
Department of Biomedical Sciences, College of Medicine, University of Illinois at Chicago, Rockford, IL61107; and Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294
Nasser
Said-Al-Naief
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294
Xu
Feng
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294
Jay M.
McDonald
Department of Pathology, University of Alabama at Birmingham, AL 35294; and Veterans Administration Medical Center, Birmingham, AL 35233
Enhanced osteoclastogenesis is an important pathological feature in several aging-associated bone diseases. Thus, research activities on osteoclastogenesis have been intense during the last ten years. There has been great progress made in this field, however, and in this review, we will focus on current advances in understanding the role of Ca2+/calmodulin signaling in osteoclastogenesis. There are two major Ca2+/calmodulin signaling pathways emerging as important in osteoclastogenesis. The first is from our recent data, which has established a specific role for calmodulin in osteoclastogenesis and, more specifically, calmodulin-dependent kinase II (CaMKII). The other is that a pathway involving RANK-Ca2+-calmodulin—calcineurin—NFAT is critical for osteoclastogenesis. Collectively, these reports highlight the importance of Ca2+/calmodulin signaling in osteoclastogenesis, which may present novel targets for the new therapeutic agents to combat bone loss.
Parathyroid Hormone-Related Protein in Prostate Cancer
15-28
10.1615/CritRevEukaryotGeneExpr.v15.i1.20
Farrokh
Asadi
Medical Service, VA Chicago Health Care System, Department of Medicine, University of Illinois College of Medicine, Chicago IL 60612
Subhash
Kukreja
Medical Service, VA Chicago Health Care System, Department of Medicine, University of Illinois College of Medicine, Chicago IL 60612
Although originally discovered as the peptide responsible for humoral hypercalcemia of malignancy (HHM), parathyroid hormone-related protein (PTHrP) has been shown to play a major role in fetal development. In the adult, it is widely distributed in normal and various cancer tissues. In spite of the rarity of HHM in prostate cancer, PTHrP is widely distributed in prostate cancer cells. PTHrP is a precursor molecule with generation of various fragments with distinct biological activities. More recent studies have shown that there is intranuclear localization of PTHrP and that intracrine effects of the peptide are involved in promoting processes that result in tumor progression (cell proliferation, apoptosis, cell attachment and angiogenesis) in prostate cancer. PTHrP expression is controlled by three distinct promoters, with P3 being used most often in cancer cells. The factors that control PTHrP production via interaction with the promoters are growth factors, androgens, vitamin D analogs, and adenoviral proteins. TGF-β and its effector Smad3 activate the P3 promoter through an AGAC box and an Ets binding site involving Ets1 and to some extent Ets2 proteins. In addition, TGF-β stimulates P3 promoter activity via Smad-independent pathways that involve the p38 MAP kinase. Although the addition of PTHrP or transfection with the PTHrP gene in prostate cells results in effects that promote tumor development, studies that employ inhibition of PTHrP activity in vitro and in vivo are needed to establish a definitive role of this peptide in the pathogenesis of prostate cancer.
Heparan Sulfate Proteoglycans: Key Players in Cartilage Biology
29-48
10.1615/CritRevEukaryotGeneExpr.v15.i1.30
Mary C.
Farach-Carson
Department of Biological Sciences, University of Delaware, Newark, DE 19716
Jacqueline T.
Hecht
Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030
Daniel D.
Carson
Department of Biological Sciences, University of Delaware, Newark, DE 19716
The extracellular matrix (ECM) plays a fundamental role in skeletal patterning and formation of the vertebrate skeleton. This review focuses on the fundamental roles associated with heparan sulfate (HS) proteoglycans in the ECM during cartilage development, which include regulation of gene expression, presentation of growth factors, establishment of morphogen gradients, and modulation of blood homeostasis. The importance of enzymes involved in biosynthesis and assembly of heparan sulfate is also discussed. Finally, the current evidence for functions of individual HS proteoglycans and biosynthetic enzymes based upon human genetic mutation associations with disease and genetic manipulation in transgenic mice is presented. These findings highlight the important role played by HS proteoglycans, such as perlecan, in cartilage development and skeletal growth.
Nuclear Transport of Steroid Hormone Receptors
49-73
10.1615/CritRevEukaryotGeneExpr.v15.i1.40
Leonard C.
Shank
Center for Cell Signaling, Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908
Bryce M.
Paschal
Center for Cell Signaling, Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908
Nuclear receptors (NRs) comprise a superfamily of ligand-regulated transcription factors implicated in a host of physiological processes, including development, differentiation, and proliferation. Translated in the cytoplasm, NRs must undergo import into the nucleus in order to modulate transcription of target genes in response to cognate hormones. NRs also undergo export from the nucleus, and there is emerging evidence that NR nucleocytoplasmic shuttling contributes to their regulation. Nucleocytoplasmic shuttling may provide a nexus for crosstalk between NRs and kinase pathways. Here we review some of the key studies on nuclear import and export of steroid hormone receptors within the NR superfamily, address some of the challenges in experimental dissection of NR transport and discuss recent findings linking specific kinase pathways to NR export.
Apoptosis in Membranous Bone Formation: Role of Fibroblast Growth Factor and Bone Morphogenetic Protein Signaling
75-92
10.1615/CritRevEukaryotGeneExpr.v15.i1.50
Olivia
Fromigue
Laboratory of Osteoblast Biology and Pathology, INSERM Unite 606, Hopital Lariboisiere, 2 rue Ambroise Pare, 75475 Paris Cedex 10, France
Dominique
Modrowski
Laboratory of Osteoblast Biology and Pathology, INSERM Unite 606, Hopital Lariboisiere, 2 rue Ambroise Pare, 75475 Paris Cedex 10, France
Pierre J.
Marie
Laboratory of Osteoblast Biology and Pathology, INSERM Unite 606, Hopital Lariboisiere, 2 rue Ambroise Pare, 75475 Paris Cedex 10, France
Membranous ossification occurs by the condensation of mesenchymal cells followed by their progressive differentiation into osteoblasts that form a mineralized matrix in ossification centers. The balance between proliferating and differentiated osteogenic cells at the suture areas between calvarial bones is essential for the control of suture maintenance and membranous bone formation. The mechanisms of regulation of cell apoptosis in suture areas begin to be understood. Fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) are important regulators of mesenchymal, preosteoblast, and osteoblast apoptosis in suture areas. Perturbations in FGF or BMP signaling lead to alter the number of apoptotic osteogenic cells, resulting in premature or delayed suture closure. Recent data indicate that FGF signaling downregulates preosteoblast apoptosis, thereby preventing premature fusion of adjacent mineralizing extremities. In contrast, continuous FGF signaling or constitutive FGF receptor activation, as well as BMP signaling, upregulate osteoblast apoptosis. Additionally, multiple signaling mechanisms, including PI3K and PKC, appear to be involved in the control of calvarial osteoblast apoptosis by FGF and BMP. These mechanisms allow a fine control of the number of functional bone-forming cells and, thereby, the normal progression of membranous bone formation.