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PERP regulates enamel formation via effects on cell-cell adhesion and gene expression.
Jheon AH, Mostowfi P, Snead ML, Ihrie RA, Sone E, Pramparo T, Attardi LD, Klein OD
(2011) J Cell Sci 124: 745-54
MeSH Terms: Ameloblasts, Animals, Cell Adhesion, Cells, Cultured, Dental Enamel, Desmosomes, Gene Expression, Gene Expression Regulation, Developmental, Membrane Proteins, Mice, Mice, Knockout, Microarray Analysis, Odontogenesis, Tooth
Show Abstract · Added August 21, 2012
Little is known about the role of cell-cell adhesion in the development of mineralized tissues. Here we report that PERP, a tetraspan membrane protein essential for epithelial integrity, regulates enamel formation. PERP is necessary for proper cell attachment and gene expression during tooth development, and its expression is controlled by P63, a master regulator of stratified epithelial development. During enamel formation, PERP is localized to the interface between the enamel-producing ameloblasts and the stratum intermedium (SI), a layer of cells subjacent to the ameloblasts. Perp-null mice display dramatic enamel defects, which are caused, in part, by the detachment of ameloblasts from the SI. Microarray analysis comparing gene expression in teeth of wild-type and Perp-null mice identified several differentially expressed genes during enamel formation. Analysis of these genes in ameloblast-derived LS8 cells upon knockdown of PERP confirmed the role for PERP in the regulation of gene expression. Together, our data show that PERP is necessary for the integrity of the ameloblast-SI interface and that a lack of Perp causes downregulation of genes that are required for proper enamel formation.
1 Communities
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14 MeSH Terms
Plakophilin-1 localizes to the nucleus and interacts with single-stranded DNA.
Sobolik-Delmaire T, Reddy R, Pashaj A, Roberts BJ, Wahl JK
(2010) J Invest Dermatol 130: 2638-46
MeSH Terms: Cell Line, Tumor, Cell Nucleus, Cell Survival, Chromatin, DNA Damage, DNA, Single-Stranded, Desmosomes, Detergents, Epithelial Cells, Humans, Octoxynol, Plakophilins, Solubility
Show Abstract · Added June 6, 2013
Plakophilins (Pkp-1, -2, and -3) comprise a family of armadillo repeat-containing proteins first identified as desmosomal plaque components, in which they link desmoplakin to the desmosomal cadherins. In addition to their role in desmosomal cell-cell adhesion, Pkps also localize to the nucleus, where they perform unknown functions. Of the three Pkps, Pkp-1 is most readily detected in the nucleus, where it is localized to the nucleoplasm. Pkp chimeras containing the Pkp-1 head domain and Pkp-3 armadillo repeat domain were localized to the nucleus in A431 cells, whereas Pkp chimeras containing the Pkp-3 head domain and Pkp-1 armadillo repeat domain localized to the desmosome and the cytosol. DNAse I digestion of chromatin in cultured cells results in loss of nuclear Pkp-1, suggesting that Pkp-1 associates specifically with nuclear components. In addition, in vitro assays revealed that the amino-terminal head domains of Pkps-1 and -2 were sufficient to bind single-stranded DNA. Induction of DNA damage induced a partial redistribution of Pkp-1 protein to the nucleolus, and depletion of Pkp-1 resulted in increased survival in response to DNA damage. These data suggest that in addition to mediating desmosome assembly, the nuclear pool of Pkp can influence cell survival by interactions with DNA.
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13 MeSH Terms
Carboxyl terminus of Plakophilin-1 recruits it to plasma membrane, whereas amino terminus recruits desmoplakin and promotes desmosome assembly.
Sobolik-Delmaire T, Katafiasz D, Wahl JK
(2006) J Biol Chem 281: 16962-16970
MeSH Terms: Amino Acid Sequence, Calcium, Cell Line, Cell Line, Tumor, Cell Membrane, Cell Nucleus, Desmoplakins, Desmosomes, Gene Deletion, Humans, Molecular Sequence Data, Plakophilins, Protein Structure, Tertiary, Sequence Homology, Amino Acid
Show Abstract · Added June 6, 2013
Plakophilins are armadillo repeat-containing proteins, initially identified as desmosomal plaque proteins that have subsequently been shown to also localize to the nucleus. Loss of plakophilin-1 is the underlying cause of ectodermal dysplasia/skin fragility syndrome, and skin from these patients exhibits desmosomes that are reduced in size and number. Thus, it has been suggested that plakophilin-1 plays an important role in desmosome stability and/or assembly. In this study, we used a cell culture system (A431DE cells) that expresses all of the proteins necessary to assemble a desmosome, except plakophilin-1. Using this cell line, we sought to determine the role of plakophilin-1 in de novo desmosome assembly. When exogenous plakophilin-1 was expressed in these cells, desmosomes were assembled, as assessed by electron microscopy and immunofluorescence localization of desmoplakin, into punctate structures. Deletion mutagenesis experiments revealed that amino acids 686-726 in the carboxyl terminus of plakophilin-1 are required for its localization to the plasma membrane. In addition, we showed that amino acids 1-34 in the amino terminus were necessary for subsequent recruitment of desmoplakin to the membrane and desmosome assembly.
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14 MeSH Terms
A new Perp in the lineup: linking p63 and desmosomal adhesion.
Ihrie RA, Attardi LD
(2005) Cell Cycle 4: 873-6
MeSH Terms: Cell Adhesion, DNA-Binding Proteins, Desmosomes, Epithelium, Genes, Tumor Suppressor, Humans, Membrane Proteins, Models, Biological, Phosphoproteins, Trans-Activators, Transcription Factors, Tumor Suppressor Proteins
Show Abstract · Added August 21, 2012
The process of stratified epithelial development depends upon a transcriptional program directed by the p53-related transcription factor p63. p63 is required for the commitment of the ectoderm to stratification and for the completion of terminal differentiation in stratified epithelia, and mutations in p63 have been identified in multiple developmental disorders affecting ectoderm-derived tissues. Recent work from our laboratory has determined that the p53 target gene Perp is required for the integrity of the stratified epithelia specified by p63, and that expression of Perp in these structures depends on the presence of p63. In these tissues, Perp is a critical component of the desmosome, a cell-cell adhesion complex whose constituents are frequently mutated in human diseases affecting the skin and hair. Perp's position downstream of p63 and p53, as well as its essential role in normal desmosome function, suggest that it, like other adhesion proteins, may be a target for mutation in human blistering diseases or cancer.
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12 MeSH Terms
Perp is a p63-regulated gene essential for epithelial integrity.
Ihrie RA, Marques MR, Nguyen BT, Horner JS, Papazoglu C, Bronson RT, Mills AA, Attardi LD
(2005) Cell 120: 843-56
MeSH Terms: Animals, Apoptosis, Cell Adhesion, Cell Differentiation, Cytoskeletal Proteins, Desmoplakins, Desmosomes, Fetal Development, Gene Expression Regulation, Developmental, Keratinocytes, Membrane Proteins, Mice, Mice, Knockout, Mouth Mucosa, Phosphoproteins, Skin, Trans-Activators
Show Abstract · Added August 21, 2012
p63 is a master regulator of stratified epithelial development that is both necessary and sufficient for specifying this multifaceted program. We show here that Perp, a tetraspan membrane protein originally identified as an apoptosis-associated target of the p53 tumor suppressor, is the first direct target of p63 clearly involved in mediating this developmental program in vivo. During embryogenesis, Perp is expressed in an epithelial pattern, and its expression depends on p63. Perp-/- mice die postnatally, with dramatic blistering in stratified epithelia symptomatic of compromised adhesion. Perp localizes specifically to desmosomes, adhesion junctions important for tissue integrity, and numerous structural defects in desmosomes are observed in Perp-deficient skin, suggesting a role for Perp in promoting the stable assembly of desmosomal adhesive complexes. These findings demonstrate that Perp is a key effector in the p63 developmental program, playing an essential role in an adhesion subprogram central to epithelial integrity and homeostasis.
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17 MeSH Terms
Coating of titanium alloy with soluble laminin-5 promotes cell attachment and hemidesmosome assembly in gingival epithelial cells: potential application to dental implants.
Tamura RN, Oda D, Quaranta V, Plopper G, Lambert R, Glaser S, Jones JC
(1997) J Periodontal Res 32: 287-94
MeSH Terms: Amino Acid Sequence, Animals, Antigens, CD, Cell Adhesion, Cell Adhesion Molecules, Cells, Cultured, Dental Alloys, Desmosomes, Epithelial Attachment, Humans, Integrin beta4, Microscopy, Electron, Molecular Sequence Data, Periodontal Diseases, Rats, Surface Properties, Titanium
Show Abstract · Added March 27, 2014
The formation of a biological seal around the transmucosal portion of dental implants may be crucial for the long-term success of these therapies. Data to date suggest that the gingival epithelium attaches to dental implants through the formation of hemidesmosomes. Biochemical and genetic data indicate that the laminin isoform, laminin-5, a component of basement membranes, plays a crucial role in the assembly and maintenance of hemidesmosomes. We report the use of soluble laminin-5 as a biological coating of titanium-alloy to promote cell attachment of the gingival epithelial cell line, IHGK. Monoclonal antibodies reactive with laminin-5 depleted the coating solution of all cell attachment activity and blocked cell attachment to laminin-5-coated disks. Immunodepletion with antibodies to fibronectin had no effect. Finally, we demonstrate that IHGK cells assembled hemidesmosomes within 24 h of attachment to laminin-5-coated titanium alloy but not to the titanium alloy alone. These results suggest that soluble laminin-5 may have clinical applications as a dental implant coating to promote the formation of a biological seal.
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17 MeSH Terms
Laminin-5 and hemidesmosomes: role of the alpha 3 chain subunit in hemidesmosome stability and assembly.
Baker SE, Hopkinson SB, Fitchmun M, Andreason GL, Frasier F, Plopper G, Quaranta V, Jones JC
(1996) J Cell Sci 109 ( Pt 10): 2509-20
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Monoclonal, Blotting, Western, Cell Adhesion Molecules, Cells, Cultured, Desmosomes, Fluorescent Antibody Technique, Indirect, Microscopy, Confocal, Molecular Sequence Data, RNA, Messenger, Rats, Sequence Homology, Amino Acid, Urinary Bladder
Show Abstract · Added March 27, 2014
Hemidesmosomes are complex macromolecular structures which integrate elements of the extracellular matrix and the cytoskeleton of epithelial cells. To characterize cell-matrix interactions in the hemidesmosome, we have made use of 804G cells which possess the unusual ability to assemble hemidesmosomes in vitro. During the course of our studies, we have raised a set of monoclonal antibodies against rat laminin-5, the major structural element comprising 804G matrix. One of these, termed CM6, recognizes the 150 kDa alpha chain of rat laminin-5 and binds the globular (G) domain of intact laminin-5 molecules as determined by rotary shadowing. CM6 antibodies perturb formed hemidesmosomes in 804G cells. In particular, within 1 hour of incubation of 804G cells with CM6 antibodies, colocalization of laminin-5 and alpha 6 beta 4 integrin is lost and by 2 hours, staining generated by hemidesmosomal antibodies appears primarily cytoplasmic in the perinuclear zone. Ultrastructurally, CM6 antibodies first appear to induce detachment of hemidesmosomes from the underlying matrix. Next, portions of the basal cell surface invaginate to form vesicles whose cytoplasmic-facing surface is coated with hemidesmosomes still associated with keratin intermediate filaments. Anchoring filaments extend into the inside compartment of the vesicles. We have also studied the impact of CM6 antibodies on a model system in which the matrix of 804G cells induces de novo assembly of hemidesmosomes in human keratinocytes. This process involves the plasma membrane reorganization of the hemidesmosome associated integrin alpha 6 beta 4 as well as a redistribution of other hemidesmosome components such as the 230 kDa bullous pemphigoid antigen. Pretreatment of 804G matrix with CM6 antibodies blocks such plasma membrane reorganization of hemidesmosome components and inhibits hemidesmosome formation. Our studies indicate a crucial role for the G domain of the alpha chain of laminin-5 in both nucleation of hemidesmosome assembly as well as maintenance of hemidesmosome structural integrity.
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14 MeSH Terms
Morphogenetic effects of soluble laminin-5 on cultured epithelial cells and tissue explants.
Baker SE, DiPasquale AP, Stock EL, Quaranta V, Fitchmun M, Jones JC
(1996) Exp Cell Res 228: 262-70
MeSH Terms: Animals, Cell Adhesion, Cell Adhesion Molecules, Cells, Cultured, Cornea, Culture Media, Conditioned, Desmosomes, Epithelial Cells, Epithelium, Humans, Keratinocytes, Kinetics, Microscopy, Electron, Morphogenesis, Organ Culture Techniques, Pancreatic Neoplasms, Rats, Tumor Cells, Cultured
Show Abstract · Added March 27, 2014
The rat cell line 804G assembles an extracellular matrix which induces not only the rapid adhesion and spreading of epithelial cells but also the assembly of a cell-matrix attachment device called the hemidesmosome. The major component of this matrix is laminin-5. We have purified rat laminin-5 from medium conditioned by 804G cells. Epithelial cells which are co-incubated with medium supplemented with soluble laminin-5 adhere and spread rapidly. Furthermore, human carcinoma cells undergo a dramatic morphologic change in the presence of laminin-5 and form orderly arrays resembling epithelial sheets. Soluble rat laminin-5 is selectively incorporated into an insoluble matrix of epithelial cells in vitro, since rat-specific laminin-5 antibodies stain cell-substrate contacts. Addition of medium containing soluble laminin-5 to explanted, human corneal rims induces assembly of hemidesmosomes, important cell-matrix attachment devices. Furthermore, rat-specific laminin-5 antibodies stain areas of contact between corneal epithelium and basement membrane, indicating that rat laminin-5 from the medium is incorporated into basement membrane. We discuss the use of laminin-5 as a medium supplement for the culture of both epithelial cells and epithelial tissue explants.
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18 MeSH Terms
A function for the integrin alpha 6 beta 4 in the hemidesmosome.
Jones JC, Kurpakus MA, Cooper HM, Quaranta V
(1991) Cell Regul 2: 427-38
MeSH Terms: Animals, Antibodies, Antigens, Surface, Cell Adhesion, Cells, Cultured, Desmosomes, Extracellular Matrix, Immunohistochemistry, Integrin alpha6beta4, Integrins, Microscopy, Immunoelectron
Show Abstract · Added March 27, 2014
Many epithelial cells appear to use cell-substratum adhesion complexes known as hemidesmosomes as the main means of anchorage to the connective tissue. Initially recognized as distinctive electron-dense images, hemidesmosomes are still poorly understood at the biochemical level. The regulation and mode of their assembly, which is disrupted in certain blistering diseases and is critical to proper wound repair, also remains to be elucidated. The integrin alpha 6 beta 4 is expressed along the basal surface of various epithelial cells. We show here that this integrin localizes to hemidesmosomes as determined by immunoelectron microscopy using antibodies directed against both the extra- and intracytoplasmic domains of alpha 6 beta 4. This result, which agrees with a recent study, suggests a functional role for the alpha 6 beta 4 integrin in the hemidesmosomes. We therefore investigated such a potential role for this integrin using the cultured rat bladder carcinoma cell line 804G, which has the uncommon ability to form hemidesmosomes in vitro when maintained on uncoated glass substrates. By immunoprecipitation and immunofluorescence, we show that 804G cells express alpha 6 beta 4 along their basal surface in a punctate pattern that overlaps with the distribution of hemidesmosomal plaque antigens. However, this pattern is altered when cells are plated in the presence of an antiserum directed against alpha 6 beta 4. Furthermore, no hemidesmosomes are detectable at the ultrastructural level in the alpha 6 beta 4 antibody-treated cells compared with control cells. These results indicate that integrins may play a critical role in assembly and adhesive functions of the hemidesmosome.
1 Communities
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11 MeSH Terms
Surface relocation of alpha 6 beta 4 integrins and assembly of hemidesmosomes in an in vitro model of wound healing.
Kurpakus MA, Quaranta V, Jones JC
(1991) J Cell Biol 115: 1737-50
MeSH Terms: Animals, Antigens, Surface, Cattle, Desmosomes, Fluorescent Antibody Technique, Integrin alpha6beta4, Microscopy, Electron, Models, Biological, Wound Healing
Show Abstract · Added March 27, 2014
A transmembrane extracellular matrix receptor of the integrin family, alpha 6 beta 4, is a component of the hemidesmosome, an adhesion complex of importance in epithelial cell-connective tissue attachment (Stepp, M. A., S. Spurr-Michaud, A. Tisdale, J. Elwell, and I. K. Gipson. 1990. Proc. Natl. Acad. Sci. USA. 87:8970-8974; Jones, J. C. R., M. A. Kurpakus, H. M. Cooper, and V. Quaranta. 1991. Cell Regulation. 2:427-438). Cytosolic components of hemidesmosomes include bullous pemphigoid (BP) antigens while extracellular components include a 125-kD component of anchoring filaments (CAF) and collagen type VII-containing anchoring fibrils. We have monitored the incorporation of the alpha 6 beta 4 integrins into forming hemidesmosomes in an in vitro wound-healing explant model. In epithelial cells recently migrated from the edges of unwounded sites over bare connective tissue, alpha 6 beta 4 first appears along the entire cell surface. At this stage, these cells contain little or no cytosolic hemidesmosomal components, at least as detectable by immunofluorescence using BP autoantibodies, whereas they are already positive for laminin and CAF. At a later stage, as cells become positive for cytosolic hemidesmosome components such as BP antigens as well as collagen type VII, alpha 6 beta 4 becomes concentrated along the basal pole of the epithelial cell where it abuts the connective tissue of the explant. Polyclonal antibodies to beta 4 do not interfere with the migration of epithelial cells in the explant. However, they prevent assembly of hemidesmosomal complexes and inhibit expression of collagen type VII in cells that have migrated over wound areas. In addition, they induce disruption of established hemidesmosomes in nonmigrating cells of the unwounded area of the explant. Monoclonal antibodies to alpha 6 have a more dramatic effect, since they completely detach epithelial cells in the unwounded area of the explant. Antibodies to CAF also detach epithelial cells in unwounded areas, apparently by inducing separation between epithelium and connective tissue at the lamina lucida of the basement membrane zone. These results suggest a model whereby polarization of alpha 6 beta 4 to the basal surface of the cells, perhaps induced by a putative anchoring filament-associated ligand, triggers assembly of hemidesmosome plaques.
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9 MeSH Terms