Extent of Laminin-5 Assembly and Secretion Effect Junctional Epidermolysis Bullosa Phenotype

Matsui, Chieko; Pereira, Phyllis; Wang, C. Kathy; Nelson, Charlotte F.; Kutzkey, Timothy; Lanigan, Caroline; Woodley, David T.; Morohashi, Masaaki; Welsh, Elizabeth A.; Hoeffler, Warren K.

doi:10.1084/jem.187.8.1273

Cited by 28 publications

(23 citation statements)

References 46 publications

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“…2A), a full-length WT chain, a mutant lacking G45 (DG45), and G45 (G45) itself. These constructs were stably expressed in laminin-332 null keratinocytes derived from a patient with JEB (JEB null ) with underlying LAMA3 gene mutations (18). As will be shown below, G45 separately expressed from the rest of the laminin-332 molecule (DG45 + G45) performed many of the same functions, albeit less efficiently (detailed below), as G45 synthesized as part of the laminin-332 molecule (WT).…”

Section: Resultsmentioning

confidence: 99%

“…Primary human keratinocytes isolated from normal skin and a patient with junctional dystrophic epidermolysis bullosa lacking laminin-332 expression due to LAMA3 mutations (18) were cultured in a 1:1 mix of defined keratinocyte serum-free medium (SFM; Life Technologies) and Medium 154 (Cascade Biologics) at 37jC in a humidified 5% CO 2 incubator. Modified human 293 PHOENIX cells (gift from Dr. G. Nolan) were cultured in DMEM supplemented with 10% FCS, 100 IU/mL penicillin, and 100 Ag/mL streptomycin at 37jC in a humidified 10% CO 2 incubator.…”

Section: Methodsmentioning

confidence: 99%

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Targeting a Tumor-Specific Laminin Domain Critical for Human Carcinogenesis

et al. 2008

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Laminin-332 is critical for squamous cell carcinoma (SCC) tumorigenesis, but targeting it for cancer therapy has been unachievable due to key role of laminin-332 in promoting tissue integrity. Here, we show that a portion of laminin-332, termed G45, which is proteolytically removed and absent in normal tissues, is prominently expressed in most human SCC tumors and plays an important role in human SCC tumorigenesis. Primary human keratinocytes lacking G45 (#G45) showed alterations of basal receptor organization, impaired matrix deposition, and increased migration. After SCC transformation, the absence of G45 domain in #G45 cells was associated with deficient extracellular signalregulated kinase and phosphotidylinositol 3-kinase (PI3K) pathway activation, impaired invasion, deficient metalloproteinase activity, and absent tumorgenicity in vivo. Expression of G45 or activated PI3K subunit in #G45 cells reversed these abnormalities. G45 antibody treatment induced SCC tumor apoptosis, decreased SCC tumor proliferation, and markedly impaired human SCC tumorigenesis in vivo without affecting normal tissue adhesion. These results show a remarkable selectivity of expression and function for laminin-332 G45 in human SCC tumorigenesis and implicate it as a specific target for anticancer therapy. [Cancer Res 2008;68(8):2885-94]

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Targeting a Tumor-Specific Laminin Domain Critical for Human Carcinogenesis

et al. 2008

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“…Does the lack of the laminin ␤2 chain result in a decreased synthesis or deposition of its potential partners in the retina? For example, disruptions in the gene encoding the ␤3 chain of laminin 5 (␣3␤3␥2) result in a failure of the other chain partners to be assembled and secreted (Matsui et al, 1995(Matsui et al, , 1998.…”

Section: Laminins In the Ipm Of Laminin ␤2 Chain-deficient Micementioning

confidence: 99%

Disruption of Laminin β2 Chain Production Causes Alterations in Morphology and Function in the CNS

et al. 1999

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From the elegant studies of Ramon y Cajal (1909) to the current advances in molecular cloning (e.g., Farber and Danciger, 1997), the retina has served as an ideal model for the entire CNS. We have taken advantage of the well described anatomy, physiology, and molecular biology of the retina to begin to examine the role of the laminins, one component of the extracellular matrix, on the processes of neuronal differentiation and synapse formation in the CNS. We have examined the effect of the deletion of one laminin chain, the ␤2 chain, on retinal development. The gross development of retinas from laminin ␤2 chain-deficient animals appears normal, and photoreceptors are formed. However, these retinas exhibit several pathologies: laminin ␤2 chain-deficient mice display abnormal outer segment elongation, abnormal electroretinograms, and abnormal rod photoreceptor synapses. Morphologically, the outer segments are reduced by 50% in length; the outer plexiform layer of mutant animals is disrupted specifically, because only 7% of observed rod invaginating synapses appear normal, whereas the inner plexiform layer is undisturbed; finally, the rate of apoptosis in the mutant photoreceptor layer is twice that of control mice. Physiologically, the electroretinogram is altered; the amplitude of the b-wave and the slope of the b-wave intensity-response function are both decreased, consistent with synaptic disruption in the outer retina. Together, these results emphasize the prominence of the extracellular matrix and, in particular, the laminins in the development and maintenance of synaptic function and morphogenesis in the CNS. Key words: synapse development; laminin; photoreceptor; ERG; apoptosis; extracellular matrixThe development and maintenance of f unctional connections within the C NS is dependent on a wide variety of processes. These include, but are not limited to, the coordinated production of different cell types, the establishment of proper connections among different cell types, and the subsequent maintenance of these connections. Many environmental factors have been suggested to play roles during these three processes (for review, see Chiba and Keshishian, 1996;Pearlman and Sheppard, 1996;Higgins et al., 1997;Hunter and Brunken, 1997). Because it is well described and continues to mature postnatally, the retina is an excellent model system in which to dissect the role of environmental factors in these three processes.We have begun to analyze the role of one element of the extracellular matrix, the laminins, in C NS development. The laminins are a complex family of extracellular glycoproteins, each composed of three independent gene products: an ␣, a ␤, and a ␥ chain. Eleven laminin chain isoforms (five ␣, three ␤, and three ␥) are known (Timpl, 1996;Koch et al., 1999), and at least 14 potential heterotrimers have been postulated (Timpl, 1996;Miner et al., 1997;Koch et al., 1999) with more, no doubt, to be identified.Mutations in several of the laminin chains are correlated with human disease. These include muta...

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“…In the skin, laminin 5 forms the anchoring filaments that link epithelial cells to the basement membrane by bridging the ␣ 6 ␤ 4 or ␣ 3 ␤ 1 integrin receptors on the cells to other forms of laminin (1,6, and 7) in the lamina densa layer of the membrane (7). Mutations in the human genes encoding each of the chains of laminin 5 can result in the junctional form of epidermolysis bullosa, a recessively inherited blistering skin disorder in which the epidermal layer separates from the dermal layer (23,24). Interestingly, laminin 5 behaves as a multifunctional protein in that it can act under certain circumstances as a motility signal and at other times as an adhesive component (2,3,25).…”

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confidence: 99%

Epithelial Cell-Specific Laminin 5 Is Required for Survival of Early Thymocytes

Kim

Lee

Lee³

et al. 2000

The Journal of Immunology

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The gene LamC2 encoding the γ2 chain of laminin 5, an epithelial cell-specific extracellular matrix protein, was identified in a PCR-based subtracted cDNA library from mouse thymic stromal cells. The mRNA existed in two alternative forms (5.1 and 2.4 kb). The full-length message was highly expressed in SCID thymus and in a nurse cell line, but not in other thymic epithelial cell lines, while the short form was more widely expressed. In situ hybridization and immunohistochemical staining revealed laminin 5 expression mostly in the subcapsular region of the adult thymus. Addition to fetal thymic organ cultures of a cell adhesion-blocking mAb to the α3 chain of laminin 5 interrupted T cell development. There was a 40% reduction in the total yield of thymocytes, and the most profound decrease (75–90%) was seen in the CD25+CD44+ and CD25+CD44−subsets of the CD4−CD8− double negative fraction. Most of the surviving double negative thymocytes expressed Sca-1, and there were significant increases in the number of cells with CD69 expression and in the fraction of annexin V-stained cells. None of these changes were observed with a nonblocking anti-laminin α3 chain mAb. These results suggest that the interaction between double negative thymoctyes and laminin 5 made by subcapsular epithelial cells is required for the survival and differentiation of mouse thymocytes.

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Extent of Laminin-5 Assembly and Secretion Effect Junctional Epidermolysis Bullosa Phenotype

Cited by 28 publications

References 46 publications

Targeting a Tumor-Specific Laminin Domain Critical for Human Carcinogenesis

Targeting a Tumor-Specific Laminin Domain Critical for Human Carcinogenesis

Disruption of Laminin β2 Chain Production Causes Alterations in Morphology and Function in the CNS

Epithelial Cell-Specific Laminin 5 Is Required for Survival of Early Thymocytes

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