Marine Le Pen and the 'New' FN:a change of style or of substance?

The electoral challenge of the far right is an enduringly problematic feature of contemporary French politics. In the first rounds of the 2012 presidential and parliamentary elections, the Front National (FN) under new leader Marine Le Pen attracted a combined total of ten million votes, bringing its ultra-nationalist policies to the centre of national political debate. This article examines the FN's impact on these elections and its implications for French politics. Drawing on official FN programmes, detailed election results and a range of opinion polling data, it assesses the strength of support for Le Pen and her party and seeks to explain their electoral appeal. In particular, it subjects to analysis the claim that the new leader has ‘de-demonised’ the FN, transforming it from perennial outsider to normal participant in mainstream French politics; and it reflects on the strategic dilemma posed for the centre-right by this newly invigorated far-right challenge.

RGD-independent cell adhesion via a tissue transglutaminase-fibronectin matrix promotes fibronectin fibril deposition and requires syndecan-4/2 and α5β1 integrin co-signaling

Fibronectin (FN) deposition mediated by fibroblasts is an important process in matrix remodeling and wound healing. By monitoring the deposition of soluble biotinylated FN, we show that the stress-induced TG-FN matrix, a matrix complex of tissue transglutaminase (TG2) with its high affinity binding partner FN, can increase both exogenous and cellular FN deposition and also restore it when cell adhesion is interrupted via the presence of RGD-containing peptides. This mechanism does not require the transamidase activity of TG2 but is activated through an RGD-independent adhesion process requiring a heterocomplex of TG2 and FN and is mediated by a syndecan-4 and ß1 integrin co-signaling pathway. By using a5 null cells, ß1 integrin functional blocking antibody, and a a5ß1 integrin targeting peptide A5-1, we demonstrate that the a5 and ß1 integrins are essential for TG-FN to compensate RGD-induced loss of cell adhesion and FN deposition. The importance of syndecan-2 in this process was shown using targeting siRNAs, which abolished the compensation effect of TG-FN on the RGD-induced loss of cell adhesion, resulting in disruption of actin skeleton formation and FN deposition. Unlike syndecan-4, syndecan-2 does not interact directly with TG2 but acts as a downstream effector in regulating actin cytoskeleton organization through the ROCK pathway. We demonstrate that PKCa is likely to be the important link between syndecan-4 and syndecan-2 signaling and that TG2 is the functional component of the TG-FN heterocomplex in mediating cell adhesion via its direct interaction with heparan sulfate chains.

Fibronectin-tissue transglutaminase matrix rescues RGD-impaired celladhesion through syndecan-4 and β integrin co-signaling

Heterotropic association of tissue transglutaminase (TG2) with extracellular matrix-associated fibronectin (FN) can restore the adhesion of fibroblasts when the integrin-mediated direct binding to FN is impaired using RGD-containing peptide. We demonstrate that the compensatory effect of the TG-FN complex in the presence of RGD-containing peptides is mediated by TG2 binding to the heparan sulfate chains of the syndecan-4 cell surface receptor. This binding mediates activation of protein kinase Ca (PKCa) and its subsequent interaction with ß1 integrin since disruption of PKCa binding to ß1 integrins with a cell-permeant competitive peptide inhibits cell adhesion and the associated actin stress fiber formation. Cell signaling by this process leads to the activation of focal adhesion kinase and ERK1/2 mitogen-activated protein kinases. Fibroblasts deficient in Raf-1 do not respond fully to the TG-FN complex unless either the full-length kinase competent Raf-1 or the kinase-inactive domain of Raf-1 is reintroduced, indicating the involvement of the Raf-1 protein in the signaling mechanism. We propose a model for a novel RGD-independent cell adhesion process that could be important during tissue injury and/or remodeling whereby TG-FN binding to syndecan-4 activates PKCa leading to its association with ß1 integrin, reinforcement of actin-stress fiber organization, and MAPK pathway activation.

Factors important to the secretion and matrix deposition of tissue transglutaminase

Data suggest that for TG2 to be secreted, an intact N-terminal FN binding site (for which TG2 has high affinity) is required, however interaction of TG2 with its high affinity binding partners presents both in the intracellular and extracellular space as well as with specific cell surface receptors may also be involved in this process. Using a site-directed mutagenesis approach, the effects of specific mutations of TG2 on its translocation to the cell surface and secretion into the ECM have been investigated. Mutations include those affecting FN binding (FN1), HSPGs binding (HS1, HS2) GTP/GDP binding site (GTP1, 2) as well as N-terminal and C-terminal domains (TG2 deletion mutants N, and C). By performing transglutaminase activity assays, cell surface protein biotinylation and verifying distribution of TG2 mutants in the ECM we demonstrated that one of the potential heparan sulfate binding site mutants (HS2 mutant) is secreted at the cell surface in a much reduced manner and is less deposited into the ECM than the HS1 mutant. The HS2 mutant showed a low affinity for binding to a heparin sepharose column demonstrating this mutation site may be a potential heparan binding site of TG2. Analogous peptides to this site were shown to have some efficiency in the inhibition of the binding of the FN-TG2 complex to cell surface heparan sulfates in a cell adhesion assay indicating the peptide to be representative of the novel heparin binding site within TG2. The GTP binding site mutants GTP1 and GTP2 exhibited low specific activity however, GTP2 showed more secretion to the cell surface in comparison to GTP1. The FN1 binding mutant did not greatly affect TG2 activity nor did it alter TG2 secretion at the cell surface and deposition into the ECM indicating that fibronectin binding at this site on the enzyme is not an important factor. Interestingly an intact N-terminus (?1-15) appeared to be essential for enzyme externalisation. Removal of the first 15 amino acids (N-terminal mutant) abolished TG2 secretion to the cell surface as well as deposition into the ECM. In addition it reduced the enzymes affinity for binding to heparin. In contrast, deletion of the C-terminal TG2 domain (?594-687) increased enzyme secretion to the cell surface. Consistent with the data presented in this thesis we speculate that TG2 must fulfill two requirements to be successfully secreted from cells. The findings indicate that the closed conformation of the enzyme as well as intact N-terminal tail and a novel HS binding site within the TG2 molecule are key elements for the enzyme’s localisation at the cell surface and its deposition into the extracellular matrix. The importance of understanding the interactions between TG2, heparan sulfates and other TG2 binding partners at the cell surface could have an impact on the design of novel strategies for enzyme inhibition which could be important in the control of extracellular TG2 related diseases.

Characterization of heparin-binding site of tissue transglutaminase:its importance in cell surface targeting, matrix deposition, and cell signaling

Tissue transglutaminase (TG2) is a multifunctional Ca2+ activated protein crosslinking enzyme secreted into the extracellular matrix (ECM), where it is involved in wound healing and scarring, tissue fibrosis, celiac disease and metastatic cancer. Extracellular TG2 can also facilitate cell adhesion important in wound healing through a non-transamidating mechanism via its association with fibronectin (FN), heparan sulphates (HS) and integrins. Regulating the mechanism how TG2 is translocated into the ECM therefore provides a strategy for modulating these physiological and pathological functions of the enzyme. Here, through molecular modelling and mutagenesis we have identified the HS binding site of TG2 202KFLKNAGRDCSRRSSPVYVGR222. We demonstrate the requirement of this binding site for translocation of TG2 into the ECM through a mechanism involving cell surface shedding of HS. By synthesizing a peptide NPKFLKNAGRDCSRRSS corresponding to the HS binding site within TG2, we also demonstrate how this mimicking peptide can in isolation compensate the RGD-induced loss of cell adhesion on FN via binding to syndecan-4, leading to activation of PKCa, pFAK-397 and ERK1/2 and the subsequent formation of focal adhesions and actin cytoskeleton organization. A novel regulatory mechanism for TG2 translocation into the extracellular compartment that depends upon TG2 conformation and the binding of HS is proposed.

TG2, a novel extracellular protein with multiple functions

TG2 is multifunctional enzyme which can be secreted to the cell surface by an unknown mechanism where its Ca(2+)-dependent transamidase activity is implicated in a number of events important to cell behaviour. However, this activity may only be transient due to the oxidation of the enzyme in the extracellular environment including its reaction with NO probably accounting for its many other roles, which are transamidation independent. In this review, we discuss the novel roles of TG2 at the cell surface and in the ECM acting either as a transamidating enzyme or as an extracellular scaffold protein involved in cell adhesion. Such roles include its ability to act as an FN co-receptor for ß integrins or in a heterocomplex with FN interacting with the cell surface heparan sulphate proteoglycan syndecan-4 leading to activation of PKCa. These different properties of TG2 involve this protein in various physiological processes, which if not regulated appropriately can also lead to its involvement in a number of diseases. These include metastatic cancer, tissue fibrosis and coeliac disease, thus increasing its attractiveness as both a therapeutic target and diagnostic marker.

A novel RGD-independent cel adhesion pathway mediated by fibronectin-bound tissue transglutaminase rescues cells from anoikis

Specific association of tissue transglutaminase (tTG) with matrix fibronectin (FN) results in the formation of an extracellular complex (tTG-FN) with distinct adhesive and pro-survival characteristics. tTG-FN supports RGD-independent cell adhesion of different cell types and the formation of distinctive RhoA-dependent focal adhesions following inhibition of integrin function by competitive RGD peptides and function blocking anti-integrin antibodies alpha5beta1. Association of tTG with its binding site on the 70-kDa amino-terminal FN fragment does not support this cell adhesion process, which seems to involve the entire FN molecule. RGD-independent cell adhesion to tTG-FN does not require transamidating activity, is mediated by the binding of tTG to cell-surface heparan sulfate chains, is dependent on the function of protein kinase Calpha, and leads to activation of the cell survival focal adhesion kinase. The tTG-FN complex can maintain cell viability of tTG-null mouse dermal fibroblasts when apoptosis is induced by inhibition of RGD-dependent adhesion (anoikis), suggesting an extracellular survival role for tTG. We propose a novel RGD-independent cell adhesion mechanism that promotes cell survival when the anti-apoptotic role mediated by RGD-dependent integrin function is reduced as in tissue injury, which is consistent with the externalization and binding of tTG to fibronectin following cell damage/stress.

The extreme right in France:from Pétain to Le Pen

The Front National has for some years been France's third political party and the most notable far-right force in Europe; its leader, Jean-Marie Le Pen, contested the 2002 presidential election run-off with 5.5 million votes. What do Le Pen and the FN represent? What are their historical roots, their values and their policies? Who votes for them and why? And what has been their impact on the political agenda in France? Adopting an essentially chronological approach, the book traces the political lineage of Le Pen and the FN through key figures, movements and events on the French extreme right from the Vichy regime to the present, providing a detailed historical perspective for understanding the FN today. Part I provides a historical study of the extreme right in France since 1940, examining • the Vichy regime, collaboration and ‘collaborationism’, • the aftermath of Liberation and the post-war extreme right, • the Poujadist movement and the politics of populism, • the Algerian War as a catalyst for change, • the ‘Nouvelle Droite’ and the search for doctrinal renewal, • old and new forms of extreme-right ideology and activism. Part II undertakes a comprehensive study of the FN, analysing • the party’s early development and electoral rise, • its evolving programme and strategy, • the factors underlying its popular appeal, • the geography and composition of its electorate, • its exercise of local power and regional influence, • and its defining impact on the national political agenda. The FN, it is argued, represents both the latest manifestation of a long tradition of authoritarian nationalism and a complex new phenomenon within the changing social and political dynamics of contemporary France.

An enigma still: Poujadism fifty years on

Few names resonate more loudly from the French Fourth Republic than that of Pierre Poujade, and few terms exude such a sulfurous odour as le poujadisme. Between 1953 and 1958, the Poujadists secured their place in modern French history, winning 52 seats in the National Assembly and inscribing a lasting entry in the lexicon of political protest. Taking as its starting point the fiftieth anniversary of Poujade’s movement held in its birthplace of Saint-Céré in July 2003, this article reassesses Poujadism fifty years on from its heyday. It considers Poujadism as the first important anti-globalisation movement in post-war France, a locus for the conflict between ‘stalemate’ traditionalism and socio-economic modernisation. It examines the trajectory of the Poujadists from anti-tax movement to political party, arguing the difficulty of defining Poujadism in classic political terms. In particular, the article takes issue with the perception of Poujadism as an extreme-right ideology and interprets it instead as a form of populist protest lacking a solid doctrinal core and opportunistic in its exploitation of political issues and allies. As such, it is argued, Poujadism represents a complex synthesis of both right-wing and left-wing values and discourses, as impervious to definition today as it was fifty years ago. The article considers the brief alliance of convenience between Poujade and Le Pen, and locates in Le Pen’s early Poujadist experience some of the methods and even some of the arguments used by the FN today. It concludes by discussing Poujade’s political activities after 1958, tracing his long-term conversion from violent opposition to the State under the Fourth Republic to co-operation under the Fifth. The author draws here on correspondence with Pierre Poujade up until his death in August 2003.

The importance of the tissue transglutaminase-fibronectin heterocomplex in the RGD-independent cell adhesion and fibronectin matrix deposition

Tissue transglutaminase (TG2) has been reported as a wound response protein. Once over-expressed by cells under stress such as during wound healing or following tissue damage, TG2 can be secreted and deposited into extracellular matrix, where it forms a heterocomplex (TG-FN) with the abundant matrix protein fibronectin (FN). A further cellular response elicited after tissue damage is that of matrix remodelling leading to the release of the Arg-Gly-Asp (RGD) containing matrix fragments by matrix matelloproteinases (MMPs). These peptides are able to block the interaction between integrin cell surface receptors and ECM proteins, leading to the loss of cell adhesion and ultimately Anoikis. This study provides a mechanism for TG2, as a stress-induced matrix protein, in protecting the cells from the RGD-dependent loss of cell adhesion and rescuing the cells from Anoikis. Mouse fibroblasts were used as a major model for this study, including different types of cell surface receptor knockout mouse embryonic fibroblasts (MEFs) (such as syndecan-4, a5, ß1 or ß3 integrins). In addition specific syndecan-2 targetting siRNAs, ß1 integrin and a4ß1 integrin functional blocking antibodies, and a specific targeting peptide against a5ß1 integrin A5-1 were used to investigate the involvement of these receptors in the RGD-independent cell adhesion on TG-FN. Crucial for TG-FN to compensate the RGD-independent cell adhesion and actin cytoskeleton formation is the direct interaction between the heparan sulfate chains of syndecan-4 and TG2, which elicits the inside-out signalling of a5ß1 integrin and the intracellular activation of syndecan-2 by protein kinase C a (PKCa). By using specific inhibitors, a cell-permeable inhibiting peptide and the detection of the phosphorylation sites for protein kinases and/or the translocation of PKCa via Western blotting, the activation of PKCa, focal adhesion kinase (FAK), ERK1/2 and Rho kinase (ROCK) were confirmed as downstream signalling molecules. Importantly, this study also investigated the influence of TG-FN on matrix turnover and demonstrated that TG-FN can restore the RGD-independent FN deposition process via an a5ß1 integrin and syndecan-4/2 co-signalling pathway linked by PKCa in a transamidating-independent manner. These data provide a novel function for TG2 in wound healing and matrix turnover which is a key event in a number of both physiological and pathological processes.

Radical or not so radical? Tactical variation in core policy formation by the Front National

Starting from a number of general tenets about radical political parties, this article examines the Front National (FN) in relation to its core policy issue of immigration. To what extent has FN immigration policy been defined from the outset by its radicalism? Has that radicalism been constant or variable over time? And how far can a reciprocal influence be detected between the FN and the center Right in immigration policy formulation? Focusing on election campaigns, manifestos, and key moments in the FN's evolution, the article assesses how the party has tailored its radicalism to contextual factors and tactical considerations. It reveals an FN less bound to a fixed policy and more ready to seek accommodation (with circumstance, public opinion, or the center Right) than is generally acknowledged. Conversely, it also assesses how the FN's mobilization of strong support on the immigration issue has had radicalizing effects on the center Right. The article concludes by considering whether the change of leadership in January 2011 might confine the FN to the radical Right or see it adopt a more center-oriented course.

Importance of syndecan-4 and syndecan -2 in osteoblast cell adhesion and survival mediated by a tissue transglutaminase-fibronectin complex

Tissue transglutaminase (TG2) has been identified as an important extracellular crosslinking enzyme involved in matrix turnover and in bone differentiation. Here we report a novel cell adhesion/survival mechanism in human osteoblasts (HOB) which requires association of FN bound TG2 with the cell surface heparan sulphates in a transamidase independent manner. This novel pathway not only enhances cell adhesion on FN but also mediates cell adhesion and survival in the presence of integrin competing RGD peptides. We investigate the involvement of cell surface receptors and their intracellular signalling molecules to further explore the pathway mediated by this novel TG-FN heterocomplex. We demonstrate by siRNA silencing the crucial importance of the cell surface heparan sulphate proteoglycans syndecan-2 and syndecan-4 in regulating the compensatory effect of TG-FN on osteoblast cell adhesion and actin cytoskeletal formation in the presence of RGD peptides. By use of immunoprecipitation and inhibitory peptides we show that syndecan-4 interacts with TG2 and demonstrate that syndecan-2 and the a5ß1 integrins, but not a4ß1 function as downstream modulators in this pathway. Using function blocking antibodies, we show activation of a5ß1 occurs by an inside out signalling mechanism involving activation and binding of protein kinase PKCa and phosphorylation of focal adhesion kinase (FAK) at Tyr861 and activation of ERK1/2.

The far right vote in France:from consolidation to collapse?

The presidential and legislative elections of 2007 are widely seen to have marked the end of the far right as a major political force in France. How could this occur only five years after Le Pen’s qualification for the presidential run-off, and with his party seemingly in the ascendant? This article discusses recent fluctuations in far-right electoral performance in France. It focuses largely on the presidential elections of 2002 and 2007, re-examining the (supposed) upswell of far-right support in 2002 and its (supposed) subsidence in 2007. Both elections require nuanced interpretation. Both confounded poll predictions, which in 2007 failed to measure the effect of Sarkozy’s hard-right campaign and, crucially, the extent to which the border between “mainstream right” and “far right” had shifted since 2002. This allowed Sarkozy to drain part of Le Pen’s electorate, and raises questions over the longer-term impact of Le Pen and the FN on the political agenda in France.

The Front National:from systematic opposition to systemic integration?

For most of its existence, the Front National (FN) fitted the classic definition of the anti-system party, opposing the founding values, institutions and elites of the Fifth Republic. Now, under Marine Le Pen's leadership, it has embarked on a strategy to integrate to the regime it once defied. Does this strategy of normalisation bear scrutiny? Using a framework drawn from Giovanni Sartori and Robert Michels, this article asks whether the FN is a one-time anti-system party that is becoming mainstream, and also whether these simple oppositional categories are adequate for understanding ideological and policy evolution in the FN's case. Through an analysis of continuity and change in FN strategy and programmes, the article shows a party torn between anti-system differentiation and institutional adaptation. It may claim to have cast out its demons but has not undertaken the necessary moderation of its programme to substantiate that claim. The FN today is on no linear path of deradicalisation but exhibits a combination of consistent, diminished and increasing radicalism across different policy areas. Despite an upward dynamic and a hugely favourable context, it remains almost entirely excluded from power and far from the breakthrough required to become a party of government.

The Front National at the polls:transformational elections or the status quo reaffirmed?

There is a widespread sense that the Front National (FN) came of age in 2014 as a challenger for power in France. The municipal and European elections appeared to herald a transformation in the party's development and prospects, demonstrating its capacity to compete as a major player at subnational and supranational levels following strong performances at the national level in the presidential and legislative elections of 2012. This article takes a critical view of that assessment. It argues that the FN in 2014 made significant progress but that the apparent surge of support for the party in these elections belies fundamental weaknesses in the depth and range of its electoral capacities and in its prospects for transforming itself into a party of government. These weaknesses were again evident in the departmental elections of 2015, confirming that the FN has not succeeded in ending bipolarisation and imposing a genuinely tripartite structure on French politics. Far from being the 'first party of France' and 'at the gates of power', the FN is still consigned primarily to a role of spoiler, with its progression stalled by institutional obstacles, electoral limitations and a political containment which it remains powerless to overcome.