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James K. Wahl - One of the best experts on this subject based on the ideXlab platform.

  • Palmitoylation of Desmoglein 2 Is a Regulator of Assembly Dynamics and Protein Turnover
    Journal of Biological Chemistry, 2016
    Co-Authors: Brett J. Roberts, Andrew P. Kowalczyk, Keith R. Johnson, My G Mahoney, Robert A. Svoboda, Andrew M. Overmiller, Joshua D. Lewis, James K. Wahl
    Abstract:

    Desmosomes are prominent adhesive junctions present between many epithelial cells as well as cardiomyocytes. The mechanisms controlling desmosome assembly and remodeling in epithelial and cardiac tissue are poorly understood. We recently identified protein palmitoylation as a mechanism regulating desmosome dynamics. In this study, we have focused on the palmitoylation of the desmosomal cadherin desmoglein-2 (Dsg2) and characterized the role that palmitoylation of Dsg2 plays in its localization and stability in cultured cells. We identified two cysteine residues in the juxtamembrane (intracellular anchor) domain of Dsg2 that, when mutated, eliminate its palmitoylation. These cysteine residues are conserved in all four desmoglein family members. Although mutant Dsg2 localizes to endogenous Desmosomes, there is a significant delay in its incorporation into junctions, and the mutant is also present in a cytoplasmic pool. Triton X-100 solubility assays demonstrate that mutant Dsg2 is more soluble than wild-type protein. Interestingly, trafficking of the mutant Dsg2 to the cell surface was delayed, and a pool of the non-palmitoylated Dsg2 co-localized with lysosomal markers. Taken together, these data suggest that palmitoylation of Dsg2 regulates protein transport to the plasma membrane. Modulation of the palmitoylation status of desmosomal cadherins can affect desmosome dynamics.

  • Palmitoylation of plakophilin is required for desmosome assembly
    Journal of Cell Science, 2014
    Co-Authors: Brett J. Roberts, Keith R. Johnson, My G Mahoney, Robert A. Svoboda, Kristen E. Johnson, Kathleen P. Mcguinn, Jintana Saowapa, James K. Wahl
    Abstract:

    Desmosomes are prominent adhesive junctions found in various epithelial tissues. The cytoplasmic domains of desmosomal cadherins interact with a host of desmosomal plaque proteins, including plakophilins, plakoglobin and desmoplakin, which, in turn, recruit the intermediate filament cytoskeleton to sites of cell-cell contact. Although the individual components of the desmosome are known, mechanisms regulating the assembly of this junction are poorly understood. Protein palmitoylation is a posttranslational lipid modification that plays an important role in protein trafficking and function. Here, we demonstrate that multiple desmosomal components are palmitoylated in vivo. Pharmacologic inhibition of palmitoylation disrupts desmosome assembly at cell-cell borders. We mapped the site of plakophilin palmitoylation to a conserved cysteine residue present in the armadillo repeat domain. Mutation of this single cysteine residue prevents palmitoylation, disrupts plakophilin incorporation into the desmosomal plaque and prevents plakophilin-dependent desmosome assembly. Finally, plakophilin mutants unable to become palmitoylated act in a dominant-negative manner to disrupt proper localization of endogenous desmosome components and decrease desmosomal adhesion. Taken together, these data demonstrate that palmitoylation of desmosomal components is important for desmosome assembly and adhesion.

  • Desmosome dynamics in migrating epithelial cells requires the actin cytoskeleton
    Experimental cell research, 2011
    Co-Authors: Brett J. Roberts, Keith R. Johnson, Anjeza Pashaj, James K. Wahl
    Abstract:

    Re-modeling of epithelial tissues requires that the cells in the tissue rearrange their adhesive contacts in order to allow cells to migrate relative to neighboring cells. Desmosomes are prominent adhesive structures found in a variety of epithelial tissues that are believed to inhibit cell migration and invasion. Mechanisms regulating desmosome assembly and stability in migrating cells are largely unknown. In this study we established a cell culture model to examine the fate of desmosomal components during scratch wound migration. Desmosomes are rapidly assembled between epithelial cells at the lateral edges of migrating cells and structures are transported in a retrograde fashion while the structures become larger and mature. Desmosome assembly and dynamics in this system are dependent on the actin cytoskeleton prior to being associated with the keratin intermediate filament cytoskeleton. These studies extend our understanding of desmosome assembly and provide a system to examine desmosome assembly and dynamics during epithelial cell migration.

  • A role for plakophilin-1 in the initiation of desmosome assembly.
    Journal of cellular biochemistry, 2005
    Co-Authors: James K. Wahl
    Abstract:

    Plakophilins (pkp-1, -2, and -3) comprise a family of armadillo-repeat containing proteins that are found in the desmosomal plaque and in the nucleus. Plakophilin-1 is most highly expressed in the suprabasal layers of theepidermis and loss of plakophilin-1 expression results in skin fragility-ectodermal dysplasia syndrome, which is characterized by a reduction in the number and size of Desmosomes in the epithelia of affected individuals. To investigate the role of plakophilin-1 during desmosome formation, we fused plakophilin-1 to the hormone-binding domain of the estrogen receptor to create a fusion protein (plakophilin-1/ER) that can be activated in cell culture by the addition of 4-hydroxytamoxifen. When plakophilin-1/ER was expressed in A431 cells it was incorporated into endogenous Desmosomes and did not disrupt desmosome formation. A derivative of A431 cells (A431 D) do not form Desmosomes, even though they express all the components believed to be necessary for desmosome assembly. Expression and activation of plakophilin-1/ER in A431D cells resulted in punctate desmoplakin staining on the cell surface. Co-expression of a classical cadherin (N-cadherin) and plakophilin-1/ER in A431 D cells resulted in punctate desmoplakin staining at cell-cell borders. These data suggest that plakophilin-1 can induce assembly of desmosomal components in A431 D cell Is in the absence of a classical cadherin; however a classical cadherin (N-cadherin) is required to direct assembly of Desmosomes between adjacent cells. The activatable plakophilin-1/ER system provides a unique culture system to study the assembly of the desmosomal plaque in culture.

  • Cross-Talk between Adherens Junctions and Desmosomes Depends on Plakoglobin
    The Journal of cell biology, 1997
    Co-Authors: Jani E. Lewis, James K. Wahl, Keith R. Johnson, Kristin M. Sass, Pamela J. Jensen, Margaret J. Wheelock
    Abstract:

    Squamous epithelial cells have both adherens junctions and Desmosomes. The ability of these cells to organize the desmosomal proteins into a functional structure depends upon their ability first to organize an adherens junction. Since the adherens junction and the desmosome are separate structures with different molecular make up, it is not immediately obvious why formation of an adherens junction is a prerequisite for the formation of a desmosome. The adherens junction is composed of a transmembrane classical cadherin (E-cadherin and/or P-cadherin in squamous epithelial cells) linked to either β-catenin or plakoglobin, which is linked to α-catenin, which is linked to the actin cytoskeleton. The desmosome is composed of transmembrane proteins of the broad cadherin family (desmogleins and desmocollins) that are linked to the intermediate filament cytoskeleton, presumably through plakoglobin and desmoplakin. To begin to study the role of adherens junctions in the assembly of Desmosomes, we produced an epithelial cell line that does not express classical cadherins and hence is unable to organize Desmosomes, even though it retains the requisite desmosomal components. Transfection of E-cadherin and/or P-cadherin into this cell line did not restore the ability to organize Desmosomes; however, overexpression of plakoglobin, along with E-cadherin, did permit desmosome organization. These data suggest that plakoglobin, which is the only known common component to both adherens junctions and Desmosomes, must be linked to E-cadherin in the adherens junction before the cell can begin to assemble desmosomal components at regions of cell–cell contact. Although adherens junctions can form in the absence of plakoglobin, making use only of β-catenin, such junctions cannot support the formation of Desmosomes. Thus, we speculate that plakoglobin plays a signaling role in desmosome organization.

Laura D Attardi - One of the best experts on this subject based on the ideXlab platform.

  • loss of the p53 p63 regulated desmosomal protein perp promotes tumorigenesis
    PLOS Genetics, 2010
    Co-Authors: Veronica G Beaudry, Rachel L Dusek, Eunice J Park, Katie Ridd, Stevan Knezevich, Dadi Jiang, Hannes Vogel, Boris C. Bastian, Laura D Attardi
    Abstract:

    Dysregulated cell–cell adhesion plays a critical role in epithelial cancer development. Studies of human and mouse cancers have indicated that loss of adhesion complexes known as adherens junctions contributes to tumor progression and metastasis. In contrast, little is known regarding the role of the related cell–cell adhesion junction, the desmosome, during cancer development. Studies analyzing expression of desmosome components during human cancer progression have yielded conflicting results, and therefore genetic studies using knockout mice to examine the functional consequence of desmosome inactivation for tumorigenesis are essential for elucidating the role of Desmosomes in cancer development. Here, we investigate the consequences of desmosome loss for carcinogenesis by analyzing conditional knockout mice lacking Perp, a p53/p63 regulated gene that encodes an important component of Desmosomes. Analysis of Perp-deficient mice in a UVB-induced squamous cell skin carcinoma model reveals that Perp ablation promotes both tumor initiation and progression. Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell–cell adhesion. Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status. Similarly, human squamous cell carcinomas display loss of PERP expression with retention of adherens junctions components, indicating that this is a relevant stage of human cancer development. Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis. Together, these studies suggest that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss, and inflammation, and they highlight a fundamental role for Perp and Desmosomes in tumor suppression. An understanding of the factors affecting cancer progression is important for ultimately improving the diagnosis, prognostication, and treatment of cancer.

  • Loss of the p53/p63 Regulated Desmosomal Protein Perp Promotes Tumorigenesis
    PLOS Genetics, 2010
    Co-Authors: Veronica G Beaudry, Rachel L Dusek, Eunice J Park, Katie Ridd, Stevan Knezevich, Dadi Jiang, Hannes Vogel, Boris C. Bastian, Laura D Attardi
    Abstract:

    Dysregulated cell–cell adhesion plays a critical role in epithelial cancer development. Studies of human and mouse cancers have indicated that loss of adhesion complexes known as adherens junctions contributes to tumor progression and metastasis. In contrast, little is known regarding the role of the related cell–cell adhesion junction, the desmosome, during cancer development. Studies analyzing expression of desmosome components during human cancer progression have yielded conflicting results, and therefore genetic studies using knockout mice to examine the functional consequence of desmosome inactivation for tumorigenesis are essential for elucidating the role of Desmosomes in cancer development. Here, we investigate the consequences of desmosome loss for carcinogenesis by analyzing conditional knockout mice lacking Perp, a p53/p63 regulated gene that encodes an important component of Desmosomes. Analysis of Perp-deficient mice in a UVB-induced squamous cell skin carcinoma model reveals that Perp ablation promotes both tumor initiation and progression. Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell–cell adhesion. Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status. Similarly, human squamous cell carcinomas display loss of PERP expression with retention of adherens junctions components, indicating that this is a relevant stage of human cancer development. Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis. Together, these studies suggest that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss, and inflammation, and they highlight a fundamental role for Perp and Desmosomes in tumor suppression. An understanding of the factors affecting cancer progression is important for ultimately improving the diagnosis, prognostication, and treatment of cancer.

Yasuo Kitajima - One of the best experts on this subject based on the ideXlab platform.

  • 150(th) anniversary series: Desmosomes and autoimmune disease, perspective of dynamic desmosome remodeling and its impairments in pemphigus.
    Cell communication & adhesion, 2014
    Co-Authors: Yasuo Kitajima
    Abstract:

    Desmosomes are the most important intercellular adhering junctions that adhere two adjacent keratinocytes directly with desmosomal cadherins, that is, desmogleins (Dsgs) and desmocollins, forming an epidermal sheet. Recently, two cell-cell adhesion states of Desmosomes, that is, "stable hyper-adhesion" and "dynamic weak-adhesion" conditions have been recognized. They are mutually reversible through cell signaling events involving protein kinase C (PKC), Src and epidermal growth factor receptor (EGFR) during Ca(2+)-switching and wound healing. This remodeling is impaired in pemphigus vulgaris (PV, an autoimmune blistering disease), caused by anti-Dsg3 antibodies. The antibody binding to Dsg3 activates PKC, Src and EGFR, linked to generation of dynamic weak-adhesion Desmosomes, followed by p38MAPK-mediated endocytosis of Dsg3, resulting in the specific depletion of Dsg3 from Desmosomes and acantholysis. A variety of pemphigus outside-in signaling may explain different clinical (non-inflammatory, inflammatory, and necrolytic) types of pemphigus. Pemphigus could be referred to a "desmosome-remodeling disease involving pemphigus IgG-activated outside-in signaling events".

  • Binding of pemphigus vulgaris IgG to antigens in desmosome core domains excludes immune complexes rather than directly splitting Desmosomes.
    The British journal of dermatology, 2010
    Co-Authors: Yumi Aoyama, Miki Nagai, Yasuo Kitajima
    Abstract:

    Summary Background  Pemphigus vulgaris (PV) is characterized by autoantibodies against desmoglein (Dsg) 3 or both Dsg1 and Dsg3, i.e. desmosomal adhesion molecules. Objectives  We examined whether or not PV IgG binding to Dsg3 directly impairs the adhesion of Desmosomes. Methods  For immunofluorescence microscopy, keratinocytes were first incubated with PV IgG for 30 min in low Ca2+ medium, in which no Desmosomes were formed, and then for 1 h in high Ca2+ medium to generate Desmosomes. For immunoelectron microscopy, after a 30-min incubation with PV IgG in low Ca2+ medium, cells were incubated with antihuman IgG with 5-nm gold particles for 5 min; after washing, cells were further incubated in high Ca2+ medium for 1 h. For tracing of PV IgG/Dsg3 immune complexes formed in the desmosomal core domain, cells were first incubated with PV IgG for 5 min to allow PV IgG to bind the desmosomal core domain and were further incubated with PV IgG-free medium for different times. Results  Immunofluorescence microscopy revealed that PV IgG bound in a random-punctate pattern on the cell surface in low Ca2+ medium was translocated to the cell–cell contacts forming a dotted-linear distribution, suggesting desmosome generation even in the presence of PV IgG. Immunoelectron microscopy revealed that half-desmosome-like structures decorated with gold particles in low Ca2+ keratinocytes coupled to form Desmosomes and gold particles were sandwiched in the desmosomal core domain after Ca2+ switch, even though their surfaces were covered with PV IgG/antihuman IgG 5-nm gold particles. In the tracing experiments, although PV IgG demonstrated a dotted-linear distribution along the cell–cell contacts colocalized with desmoplakin (DPK) after a 30-min tracing, it disappeared from cell–cell contacts after a 5-h tracing, leaving DPK and desmocollin 3. Conclusions  These results suggest that the PV IgG/Dsg3 immune complexes are excluded from the desmosomal core domain rather than directly splitting the desmosome.

  • Mechanisms of desmosome assembly and disassembly
    Clinical and experimental dermatology, 2002
    Co-Authors: Yasuo Kitajima
    Abstract:

    In skin, Desmosomes constitute critical adhesion complexes between adjacent keratinocytes that help maintain an intact epidermis. However, individual keratinocytes need to migrate and differentiate and therefore Desmosomes must have an inherent dynamic capacity to assemble and disassemble. This review highlights the role of the different structural junctional components involved in desmosome formation and turnover, as well as the possible signalling processes and pathways that may be implicated in desmosome homeostasis. Clues to the intricate nature of desmosome assembly and disassembly have been derived from human inherited and acquired blistering skin diseases as well as animal models and basic cell biology studies. The key implications for understanding desmosome dynamics from these findings are summarized in this review.

  • assembly pathway of desmoglein 3 to Desmosomes and its perturbation by pemphigus vulgaris igg in cultured keratinocytes as revealed by time lapsed labeling immunoelectron microscopy
    Laboratory Investigation, 2000
    Co-Authors: Miki Sato, Yumi Aoyama, Yasuo Kitajima
    Abstract:

    To determine the assembly pathway of desmoglein 3 (Dsg3) into Desmosomes and the subsequent effects of pemphigus vulgaris immunoglobulin G (PV-IgG) on such, we employed a time-lapsed labeling for FITC/Rhodamine (Rod) double-stained immunofluorescence and 5-nm/10-nm gold double-stained immunoelectron microscopy by using PV-IgG, which was confirmed to react specifically Dsg3. Cells from a human squamous cell carcinoma cell line (DJM-1) were first treated briefly with PV-IgG (3 min), then incubated in either anti-human IgG-FITC or 5-nm gold antibody-containing medium (5 min), followed by a 60-minute chase in normal medium without antibodies. The same cells were reincubated with PV-IgG medium for 3 minutes, followed by either anti-human IgG-Rod or 10-nm gold antibodies for 5 minutes. Using this method, FITC and 5-nm gold particles show the fate of Dsg3-PV-IgG complexes during the following 60-minute chase. IgG-Rod or 10-nm gold particles, which are bound during the last 5 minutes of the chase, show Dsg3 molecules newly expressed on the cell surface during the 60-minute-chase period. Initially, Dsg3 formed two types of small clusters on the nondesmosomal plasma membrane, ie, either half-desmosome-like clusters with keratin intermediate filament (KIF) attachment or simple clusters without KIF attachment. The PV-IgG binding to Dsg3 caused the internalization of the simple clusters into endosomes, but not the half-desmosome-like clusters. After the 60-minute-chase period, both types of cell surface Dsg3 clusters were labeled with only 10-nm gold, suggesting that new Dsg3 molecules were being delivered to the cell surface. Desmosomes were labeled with both 5-nm gold and 10-nm gold, whereas the half-desmosome-like clusters were labeled with only 10-nm gold, suggesting that the Desmosomes themselves were not split. These results suggest that Dsg3 first forms simple clusters, followed by KIF-attachment, and then becomes integrated into Desmosomes, and that PV-IgG-induced internalization of the nondesmosomal simple clusters of Dsg3 may represent the primary effects of PV-IgG on keratinocytes.

  • transmembrane signaling for adhesive regulation of Desmosomes and hemiDesmosomes and for cell cell detachment induced by pemphigus igg in cultured keratinocytes involvement of protein kinase c
    Journal of Investigative Dermatology Symposium Proceedings, 1999
    Co-Authors: Yasuo Kitajima, Yumi Aoyama, Mariko Seishima
    Abstract:

    We have investigated transmembrane signaling for the regulation of Desmosomes and hemiDesmosomes, using a human squamous cell carcinoma cell line (DJM-1) and normal human keratinocytes. This review discusses the involvement of protein kinase C (PKC) in regulation of these junctions, and signaling pathways involved in cell-cell detachment induced by pemphigus vulgaris (PV) IgG in a culture system. Cells grown in low-Ca++ conditions, which lack Desmosomes, rapidly form Desmosomes upon a low-normal Ca+-shift in association with PKC-activation and, in turn, PKC-activation by 12-O-tetradecanoylphorbol-13-acetate (TPA) induces desmosome formation even in low-Ca++ conditions. TPA induces serine-phosphorylation of the 180 kDabullous pemphigoid antigen (BPAG2), generating 190 kDa-phosphorylated BPAG2, and dissociates BPAG2 from hemiDesmosomes. TPA-treatment also causes secretion of urokinase-type plasminogen activator (uPA) and expression of its receptor (uPAR), which activates plasminogen to plasmin and may digest extracellular domains of Desmosomes and hemiDesmosomes. These results suggest that PKC may play a role in activation of desmosome turnover and dysfunction of hemidesmossomes, and thus a role in up-migration of keratinocytes. Binding of PV-IgG to Dsg3 induces activation of diverse isoenzymes of PKC, linked to uPA secretion and uPAR expression. Furthermore, PV-IgG binding alone induces the serine-phosphorylation of Dsg 3, associated with its dissociation from plakoglobin and its deletion from Desmosomes. This PV-IgG-induced Dsg 3-phosphoryl- ation and Dsg 3-deletion from Desmosomes may impair desmosome formation, whereas PV-IgG-induced PKC signaling mediates the uPA secretion and uPAR expression leading to digestion of preexisting Desmosomes from the outside of the cell. These two different PV-IgG-activated signaling pathways may play a key role in acantholysis in PV.

Veronica G Beaudry - One of the best experts on this subject based on the ideXlab platform.

  • loss of the p53 p63 regulated desmosomal protein perp promotes tumorigenesis
    PLOS Genetics, 2010
    Co-Authors: Veronica G Beaudry, Rachel L Dusek, Eunice J Park, Katie Ridd, Stevan Knezevich, Dadi Jiang, Hannes Vogel, Boris C. Bastian, Laura D Attardi
    Abstract:

    Dysregulated cell–cell adhesion plays a critical role in epithelial cancer development. Studies of human and mouse cancers have indicated that loss of adhesion complexes known as adherens junctions contributes to tumor progression and metastasis. In contrast, little is known regarding the role of the related cell–cell adhesion junction, the desmosome, during cancer development. Studies analyzing expression of desmosome components during human cancer progression have yielded conflicting results, and therefore genetic studies using knockout mice to examine the functional consequence of desmosome inactivation for tumorigenesis are essential for elucidating the role of Desmosomes in cancer development. Here, we investigate the consequences of desmosome loss for carcinogenesis by analyzing conditional knockout mice lacking Perp, a p53/p63 regulated gene that encodes an important component of Desmosomes. Analysis of Perp-deficient mice in a UVB-induced squamous cell skin carcinoma model reveals that Perp ablation promotes both tumor initiation and progression. Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell–cell adhesion. Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status. Similarly, human squamous cell carcinomas display loss of PERP expression with retention of adherens junctions components, indicating that this is a relevant stage of human cancer development. Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis. Together, these studies suggest that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss, and inflammation, and they highlight a fundamental role for Perp and Desmosomes in tumor suppression. An understanding of the factors affecting cancer progression is important for ultimately improving the diagnosis, prognostication, and treatment of cancer.

  • Loss of the p53/p63 Regulated Desmosomal Protein Perp Promotes Tumorigenesis
    PLOS Genetics, 2010
    Co-Authors: Veronica G Beaudry, Rachel L Dusek, Eunice J Park, Katie Ridd, Stevan Knezevich, Dadi Jiang, Hannes Vogel, Boris C. Bastian, Laura D Attardi
    Abstract:

    Dysregulated cell–cell adhesion plays a critical role in epithelial cancer development. Studies of human and mouse cancers have indicated that loss of adhesion complexes known as adherens junctions contributes to tumor progression and metastasis. In contrast, little is known regarding the role of the related cell–cell adhesion junction, the desmosome, during cancer development. Studies analyzing expression of desmosome components during human cancer progression have yielded conflicting results, and therefore genetic studies using knockout mice to examine the functional consequence of desmosome inactivation for tumorigenesis are essential for elucidating the role of Desmosomes in cancer development. Here, we investigate the consequences of desmosome loss for carcinogenesis by analyzing conditional knockout mice lacking Perp, a p53/p63 regulated gene that encodes an important component of Desmosomes. Analysis of Perp-deficient mice in a UVB-induced squamous cell skin carcinoma model reveals that Perp ablation promotes both tumor initiation and progression. Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell–cell adhesion. Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status. Similarly, human squamous cell carcinomas display loss of PERP expression with retention of adherens junctions components, indicating that this is a relevant stage of human cancer development. Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis. Together, these studies suggest that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss, and inflammation, and they highlight a fundamental role for Perp and Desmosomes in tumor suppression. An understanding of the factors affecting cancer progression is important for ultimately improving the diagnosis, prognostication, and treatment of cancer.

Lisa M Domke - One of the best experts on this subject based on the ideXlab platform.

  • The cell–cell junctions of mammalian testes: I. The adhering junctions of the seminiferous epithelium represent special differentiation structures
    Cell and Tissue Research, 2014
    Co-Authors: Lisa M Domke, Hans Heid, Ralf Zimbelmann, Steffen Rickelt, Yvette Dorflinger, Caecilia Kuhn, Stefanie Winter-simanowski, Rina Rosin-arbesfeld, Werner W Franke
    Abstract:

    The seminiferous tubules and the excurrent ducts of the mammalian testis are physiologically separated from the mesenchymal tissues and the blood and lymph system by a special structural barrier to paracellular translocations of molecules and particles: the “blood–testis barrier”, formed by junctions connecting Sertoli cells with each other and with spermatogonial cells. In combined biochemical as well as light and electron microscopical studies we systematically determine the molecules located in the adhering junctions of adult mammalian (human, bovine, porcine, murine, i.e., rat and mouse) testis. We show that the seminiferous epithelium does not contain Desmosomes, or “desmosome-like” junctions, nor any of the desmosome-specific marker molecules and that the adhering junctions of tubules and ductules are fundamentally different. While the ductules contain classical epithelial cell layers with E-cadherin-based adherens junctions (AJs) and typical Desmosomes, the Sertoli cells of the tubules lack Desmosomes and “desmosome-like” junctions but are connected by morphologically different forms of AJs. These junctions are based on N-cadherin anchored in cytoplasmic plaques, which in some subforms appear thick and dense but in other subforms contain only scarce and loosely arranged plaque structures formed by α- and β-catenin, proteins p120, p0071 and plakoglobin, together with a member of the striatin family and also, in rodents, the proteins ZO-1 and myozap. These N-cadherin-based AJs also include two novel types of junctions: the “ areae adhaerentes ”, i.e., variously-sized, often very large cell-cell contacts and small sieve-plate-like AJs perforated by cytoplasm-to-cytoplasm channels of 5–7 nm internal diameter (“cribelliform junctions”). We emphasize the unique character of this epithelium that totally lacks major epithelial marker molecules and structures such as keratin filaments and desmosomal elements as well as EpCAM- and PERP-containing junctions. We also discuss the nature, development and possible functions of these junctions.

  • the cell cell junctions of mammalian testes i the adhering junctions of the seminiferous epithelium represent special differentiation structures
    Cell and Tissue Research, 2014
    Co-Authors: Ralf Zimbelmann, Lisa M Domke, Steffen Rickelt, Yvette Dorflinger, Caecilia Kuhn, Stefanie Wintersimanowski, Rina Rosinarbesfeld, Hans Heid
    Abstract:

    The seminiferous tubules and the excurrent ducts of the mammalian testis are physiologically separated from the mesenchymal tissues and the blood and lymph system by a special structural barrier to paracellular translocations of molecules and particles: the “blood–testis barrier”, formed by junctions connecting Sertoli cells with each other and with spermatogonial cells. In combined biochemical as well as light and electron microscopical studies we systematically determine the molecules located in the adhering junctions of adult mammalian (human, bovine, porcine, murine, i.e., rat and mouse) testis. We show that the seminiferous epithelium does not contain Desmosomes, or “desmosome-like” junctions, nor any of the desmosome-specific marker molecules and that the adhering junctions of tubules and ductules are fundamentally different. While the ductules contain classical epithelial cell layers with E-cadherin-based adherens junctions (AJs) and typical Desmosomes, the Sertoli cells of the tubules lack Desmosomes and “desmosome-like” junctions but are connected by morphologically different forms of AJs. These junctions are based on N-cadherin anchored in cytoplasmic plaques, which in some subforms appear thick and dense but in other subforms contain only scarce and loosely arranged plaque structures formed by α- and β-catenin, proteins p120, p0071 and plakoglobin, together with a member of the striatin family and also, in rodents, the proteins ZO-1 and myozap. These N-cadherin-based AJs also include two novel types of junctions: the “areae adhaerentes”, i.e., variously-sized, often very large cell-cell contacts and small sieve-plate-like AJs perforated by cytoplasm-to-cytoplasm channels of 5–7 nm internal diameter (“cribelliform junctions”). We emphasize the unique character of this epithelium that totally lacks major epithelial marker molecules and structures such as keratin filaments and desmosomal elements as well as EpCAM- and PERP-containing junctions. We also discuss the nature, development and possible functions of these junctions.