Developmental Expression of Nicein Adhesion Protein (Laminin-5) Subunits Suggests Multiple Morphogenic Roles

Aberdam, Daniel; Aguzzi, Adriano; Baudoin, Christian; Galliano, M.; Ortonne, Jean‐Paul; Meneguzzi, Guerríno

doi:10.3109/15419069409004431

Cited by 112 publications

(98 citation statements)

References 44 publications

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“…Since AP-1 consists of proteins from the Jun and Fos families that associate as homodimers (Jun⅐Jun) or heterodimers (Fos⅐Jun), one clue might be the composition of the AP-1 dimers, meaning that a certain combination of Fos⅐Jun complexes may be necessary to provide different levels of transcriptional activity, depending on the stage of keratinocyte differentiation. It should be noted that laminin ␣3A transcripts are produced only by proliferating basal keratinocytes in vivo (33) and in vitro (15). We have shown here that the lama3A promoter AP-1 sites are preferentially bound by the Fra-2⅐JunD complex and that the binding is significantly increased by TGF-␤ stimulation of PAM212 keratinocytes as compared with untreated cells.…”

Section: Discussionmentioning

confidence: 99%

Three Activator Protein-1-binding Sites Bound by the Fra-2·JunD Complex Cooperate for the Regulation of Murine Laminin α3A (lama3A) Promoter Activity by Transforming Growth Factor-β

Virolle¹,

Monthouel²,

Djabari³

et al. 1998

Journal of Biological Chemistry

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Several lines of evidence suggest a role for laminin-5 in skin wound healing. We report here that transforming growth factor-␤ (TGF-␤), which elicits various responses during cutaneous healing, stimulates transcription of the mouse laminin ␣3A (lama3A) gene. To identify the TGF-␤-responsive elements (TGF␤-REs) on the lama3A promoter, we have generated a series of 5-deletions of the promoter upstream of the ␤-galactosidase reporter gene. Transient cell transfection assays using mouse PAM212 keratinocytes revealed that TGF␤-REs lie between nucleotides ؊297 and ؊54 relative to the transcription start site. Insertion of the TGF␤-RE in front of the unresponsive minimal SV40 promoter conferred TGF-␤ inducibility. Computer analysis of the promoter sequence identified three canonical activator protein-1 (AP-1) sites located at nucleotides ؊277 (AP-1A), ؊125 (AP-1B), and ؊69 (AP-1C). Site-directed mutagenesis of either the AP-1A or AP-1C site did not drastically alter the basal activity of the lama3A promoter, but reduced TGF-␤ responsiveness by 50%. Simultaneous mutation of these two AP-1 sites resulted in a 65% decline in the response to TGF-␤, suggesting a cooperative contribution of each site to the overall promoter activity. In contrast, mutation of the AP-1B site markedly reduced the basal activity of the lama3A promoter, indicating that this AP-1 site is essential for gene expression. Mobility shift assays demonstrated specific binding of Fra-2 and JunD to the AP-1 sites, suggesting for the first time a possible regulatory function for the Fra-2⅐JunD AP-1 complex in a basal keratinocyte-specific gene.Laminin-5 is the major adhesion ligand present in the basement membranes of stratified squamous epithelia (1, 2). In the skin, this adhesive protein is secreted by the basal keratinocytes and colocalize with the anchoring filaments of the lamina lucida of the dermal epidermal junction (3-5). Laminin-5 binds to integrin ␣ 3 ␤ 1 in focal adhesions and interacts with hemidesmosomes via ␣ 6 ␤ 4 to form a stable anchorage complex (6, 7). Laminin-5 is a heterotrimeric glycoprotein composed of the ␣3A, ␤3, and ␥2 polypeptide chains that are products of different genes. Mutations in the genes encoding laminin ␣3 (LA-MA3), ␤3 (LAMB3), and ␥2 (LAMC2) have been shown to underlie the Herlitz or non-Herlitz forms of junctional epidermolysis bullosa, characterized by blister formation and erosions of the skin and mucosas that frequently lead to neonatal death (8 -13).Several lines of evidence suggest a role for laminin-5 in the re-epithelialization of wound skin repair. Laminin-5 is found at the epidermal-dermal junction at sites and times that coincide with actively migrating or rapidly proliferating basal keratinocytes (14, 15). Moreover, enhancement of laminin-5 transcription is observed at low cell densities in vitro in migrating and proliferating keratinocytes, similar to what happens at the wound edge (15). Although the function of laminin-5 in wound healing remains to be clarified, its major dual contribution would be to all...

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Section: Discussionmentioning

confidence: 99%

Three Activator Protein-1-binding Sites Bound by the Fra-2·JunD Complex Cooperate for the Regulation of Murine Laminin α3A (lama3A) Promoter Activity by Transforming Growth Factor-β

Virolle¹,

Monthouel²,

Djabari³

et al. 1998

Journal of Biological Chemistry

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“…The rabbit polyclonal antibody against the b1 subunit and the rat monoclonal antibody GoH3 against a6 were kindly supplied by S Johansson (University Uppsala, Sweden) and A Sonnenberg (Netherlands Cancer Institute, Amsterdam, The Netherlands), respectively. The rabbit polyclonal antibodies SE152 recognizing the a3 chain and SE153 detecting the g2 chain of murine laminin 5 were a kind gift from D Aberdam (Faculte´de Me´decine, Nice, France; Aberdam et al, 1994). The rabbit polyclonal antibody L132 specific for laminin 5 was kindly provided by P Rousselle (IBCP, Lyon, France).…”

Section: Antibodiesmentioning

confidence: 99%

Tumor cell invasiveness correlates with changes in integrin expression and localization

et al. 2005

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In nontumorigenic mammary epithelial cells (EpH4), transforming growth factor-b (TGFb1) causes cell cycle arrest/apoptosis, but induces epitheliomesenchymal transition (EMT) in Ha-Ras-transformed EpH4 cells (EpRas). EMT is closely correlated with late-stage tumor progression and results in fibroblastic, migratory cells displaying a mesenchymal gene expression program (FibRas). EpRas and FibRas cells showed strongly increased cell substrate adhesion to fibronectin, collagens I/IV and laminin 1. Furthermore, Ras transformation caused enhanced or de-novo expression of the integrin subunits b1, a2 and a3, or a5 and a6, respectively, the latter subunits being even more strongly expressed in FibRas cells. Importantly, polarized EpRas cells expressed integrin subunits b1 and a6 at distinct (apical and lateral) membrane domains, while FibRas cells coexpressed these integrins and a5 at the entire plasma membrane. During EMT, EpRas cells formed an a5b1 complex and deposited its ligand fibronectin into the extracellular matrix. Function-blocking a5 antibodies attenuated migration, and caused massive apoptosis in EpRas cells undergoing TGFb1-induced EMT in collagen gels, but failed to affect EpRas-or FibRas-derived structures. We conclude that functional a5b1 integrin is centrally implicated in EMT induction. Importantly, FibRas cells also failed to deposit the a6b4 ligand laminin 5, suggesting that a6b4 is no longer functional after EMT and replaced by mesenchymal integrins such as a5b1.

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“…Focal dermal hypoplasia syndrome is known to have a marked enamel hypoplasia phenotype, but the OMIM description only notes hypoplastic teeth (Murakami et al 2011). Genetic mutations affecting epithelial integrity can also be associated with developmental enamel defects (e.g., laminin 5; Aberdam et al 1994). Maintaining an intact sheath of ameloblasts is essential for controlling the microenvironment critical for enamel biomineralization.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic mutations can directly affect the oral epithelium, thereby altering the differentiation or function of the ameloblasts or adjacent supporting cells (e.g., stratum intermedium). For example, junctional epidermolysis bullosa (Online Mendelian Inheritance of Man [OMIM] 226700, 226650) is associated with enamel hypoplasia secondary to abnormal laminin 5 formation that is critical for cell attachment (Wright et al 1993;Aberdam et al 1994). There are many syndromes caused by genes that are expressed by the oral epithelium and ameloblasts and that have an associated enamel phenotype.…”

Section: Introductionmentioning

confidence: 99%

The Molecular Basis of Hereditary Enamel Defects in Humans

2014

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The formation of human enamel is highly regulated at the molecular level and involves thousands of genes. Requisites for development of this highly mineralized tissue include cell differentiation; production of a unique extracellular matrix; processing of the extracellular matrix; altering of cell function during different stages of enamel formation; cell movement and attachment; regulation of ion and protein movement; and regulation of hydration, pH, and other conditions of the microenvironment, to name just a few. Not surprising, there is a plethora of hereditary conditions with an enamel phenotype. The objective of this review was to identify the hereditary conditions listed on Online Mendelian Inheritance in Man (OMIM) that have an associated enamel phenotype and whether a causative gene has been identified. The OMIM database was searched with the terms amelogenesis, enamel, dental, and tooth, and all results were screened by 2 individuals to determine if an enamel phenotype was identified. Gene and gene product function was reviewed on OMIM and from publications identified in PubMed. The search strategy revealed 91 conditions listed in OMIM as having an enamel phenotype, and of those, 71 have a known molecular etiology or linked genetic loci. The purported protein function of those conditions with a known genetic basis included enzymes, regulatory proteins, extracellular matrix proteins, transcription factors, and transmembrane proteins. The most common enamel phenotype was a deficient amount of enamel, or enamel hypoplasia, with hypomineralization defects being reported less frequently. Knowing these molecular defects allows an initial cataloging of molecular pathways that lead to hereditary enamel defects in humans. This knowledge provides insight into the diverse molecular pathways involved in enamel formation and can be useful when searching for the genetic etiology of hereditary conditions that involve enamel.

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Developmental Expression of Nicein Adhesion Protein (Laminin-5) Subunits Suggests Multiple Morphogenic Roles

Cited by 112 publications

References 44 publications

Three Activator Protein-1-binding Sites Bound by the Fra-2·JunD Complex Cooperate for the Regulation of Murine Laminin α3A (lama3A) Promoter Activity by Transforming Growth Factor-β

Three Activator Protein-1-binding Sites Bound by the Fra-2·JunD Complex Cooperate for the Regulation of Murine Laminin α3A (lama3A) Promoter Activity by Transforming Growth Factor-β

Tumor cell invasiveness correlates with changes in integrin expression and localization

The Molecular Basis of Hereditary Enamel Defects in Humans

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