Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

NF-κB Family

  • Lara Valiño-Rivas
  • Laura Gonzalez-Lafuente
  • Ana B. Sanz
  • Jonay Poveda
  • Alberto Ortiz
  • Maria D. Sanchez-Niño
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_220

Synonyms

List of Discussed NF-κB Family Members and Regulatory Molecules

NFκB1: p105, p50, KBF1, EBP-1

RelA: p65, NFKB3

RelB: I-REL

REL: c-Rel

NFκB2: p100, p52; LYT10

Bcl-3: BCL4, D19S37

NFKBIA: IκBα, IKBA, MAD-3, NFKBI

NFKBIB: IκBβ, IKBB, TRIP9

NFKBIE: IκBε, IKBE

NFKBIZ: IκBζ, IKBZ, INAP, MAIL

CHUK: IKKα, IKBKA, IKK1, IKKA, NFKBIKA, TCF16

IKBKB: IKKβ, IKK2, IKKB, NFKBIKB

IKBKG: IKKγ, NEMO, AMCBX1, FIP-3, FIP3, Fip3p, IP, IP1, IP2, IPD2, IKKAP1, IKKG

IKBKE: IKKε, IKKE, IKKI

MAP3K14: NIK, HS, HSNIK

TNFAIP3: A20, OTUD7C, TNFA1P2

OTUD7B: CEZANNE

CYLD: HSPC057, CDMT, CYLD1, CYLDI, EAC, MFT1, SBS, TEM, USPL2

Historical Background: Discovery and Structure

NF-κB (nuclear factor-kappa-light-chain-enhancer of activated B cells) is a collective term for a family of transcription factors. NF-κB has a complex regulation, modulates the expression of a wide set of genes, both by promoting and by suppressing gene expression and biological responses and is involved in a variety of diseases. The dysfunction of NF-κB is associated with inflammatory disease, cardiovascular injury, cancer, diabetes, kidney injury, viral infections, and human genetic disorders, among others (Kumar et al. 2004).

NF-κB was identified as a protein that bound to a specific decameric DNA sequence (ggg ACT TTC C), within the intronic enhancer of the immunoglobulin kappa light chain in mature B and plasma cells but not pre B cells (Sen and Baltimore 1986). NF-κB DNA-binding activity was induced by a variety of exogenous stimuli, was independent from de novo protein synthesis, and was bound to several DNA sequences.

NF-κB family members share structural homology with the retroviral oncoprotein v-Rel, resulting in their classification as NF-κB/Rel proteins (Gilmore 2006). There are five NF-κB proteins in the mammalian NF-κB family: RelA (p65), RelB, c-Rel, p50 (NFκB1, generated from p105), and p52 (NFκB2, generated from p100). All of them may form homo- and heterodimeric complexes. The most common and best characterized active form is the RelA/p50 heterodimer (Hayden and Ghosh 2004).

Each member of the NF-κB family has a conserved N-terminal region termed the Rel homology domain (RHD). The Rel homology domain mediates the DNA binding, dimerization, and nuclear transport of the NF-κB proteins (Li and Verma 2002). However, the transcription activator domain (TAD) necessary for target gene expression is present only in the carboxyl terminus of RelA, c-Rel, and RelB subunits. Large precursors, p105 and p100, undergo processing to generate mature p50 and p52, respectively. The p50 and p52 NF-κB subunits do not contain transactivation domains. However, they participate in target gene transactivation by forming heterodimers with RelA, RelB, or c-Rel (Li and Verma 2002). The p50 and p52 homodimers also bind to the nuclear protein Bcl-3, and such complexes can function as transcriptional activators.

NF-κB Activation

Activation of NF-κB requires a number of discrete steps (Fig. 1). There is a long list of known inducers of NF-κB activity, including many inflammatory cytokines such as TNF-α superfamily cytokines and IL-1, T cell activation signals, growth factors, reactive oxygen species (ROS), bacterial lipopolysaccharide (LPS), and other microbial products that activate toll-like receptors (TLRs) and other stress inducers ( http://people.bu.edu/gilmore/nf-kb/inducers/index.html).
NF-κB Family, Fig. 1

A representation of canonical and noncanonical NF-κB pathway activation. In the canonical pathway, IKK activation leads to proteasomal IκB degradation, which allows nuclear migration of RelA/p50 and other complexes. In the noncanonical pathway, NIK and IKKα recruitment leads to proteasomal processing of p100 to p52, allowing nuclear migration of RelB/p52 complexes. p100 may also retain RelA, c-Rel, and p50 in the cytoplasm. Thus, proteasomal processing of p100 to p52 also generates RelA/p52, c-Rel/p52, or p52/p50 complexes. IκB molecules weakly sequester RelB/p52 complexes, and they are free for nuclear translocation upon p100 processing. In the hybrid pathway, noncanonical p100 processing generates RelA/p52 and c-Rel/p52 complexes that are retained in the cytosol by IκB proteins. Classical pathway degradation of IκB proteins allows nuclear migration of these complexes. P phosphorylation, Ub ubiquitin

In the cytoplasm of almost all cell types, inactive NF-κB is associated with inhibitory κB proteins (IκBs) that regulate NF-κB nuclear translocation and DNA binding (Sanz et al. 2010a). IκBs are a class of inhibitor proteins that contain an N-terminal regulatory domain, followed by multiple copies of a sequence called ankyrin repeats and a COOH-terminal PEST domain that is important in regulating IκB turnover. The ankyrin repeats mediate the association between IκBs and NF-κB dimers and mask the nuclear localization signals (NLS) of NF-κB proteins, thus preventing nuclear translocation and keeping them in an inactive state in the cytoplasm. The most important IκBs are IκBα (associated with transient NF-κB activation), IκBβ (involved in sustained activation), and IκBε. Additional IκBs are Bcl-3, NFκBiz, p100, and p105. Bcl-3 and NFκBiz do not induce cytoplasmic retention of NF-κB, but regulates gene expression as transcriptional co-activators for p50 and p52 homodimers in the nucleus.

The phosphorylation, ubiquitination, and subsequent degradation by the 26S proteasome of ΙκB proteins are a key step in NF-κB activation that release active NF-κB (Karin and Delhase 2000). NF-κB activation is initiated by signal-induced phosphorylation of IκBs, mediated by a high-molecular-weight complex that contains a serine-specific IκB kinase (IKK). IKKs have 52% amino acid identity and a similar structural organization, which includes kinase, leucine zipper, and helix-loop-helix domains. IKKs form both homo- and heterodimers. Gene disruption studies of IKK genes in mice indicate that IKKβ is the critical kinase involved in activating the NF-κB pathway, while IKKα likely plays an accessory role (Yamamoto and Gaynor 2001). The IKK complex consists of three subunits, including the kinases IKKα and IKKβ (catalytic subunits also called IKK-1 and IKK-2, respectively) (Sanz et al. 2010a), and the regulatory nonenzymatic subunit IKK-γ (NEMO, NF-κB essential modulator) (Sanz et al. 2010a). IKKs are key convergence steps for multiple signaling pathways that lead to NF-κB activation.

There is a temporal and selective control of NF-κB target gene activation. Some genes are transcribed following a short stimulation of NF-κB. These include negative regulators of NF-κB activity such as IκBα and inflammatory cytokines such as IL-6 and MCP-1. Other genes are transcribed only when NF-κB activation occurs for at least 1 h, such as cell-surface receptors, adhesion molecules, and some chemokines such as RANTES/CCL5 (Hoffmann et al. 2002). DNA accessibility contributes in part to these temporal patterns. Cells respond sensitively to time-varying inputs in complex and dynamically changing signaling environments to achieve efficient gene expression regulation. As an example, NF-κB dynamics synchronize with oscillating TNF signal and become entrained, leading to significantly increased NF-κB oscillation amplitude and mRNA output compared to non-entrained response. This allows cells to achieve efficient gene expression in dynamically changing signaling environments. (Kellogg and Tay 2015). A switchlike response in NF-κB activity implies the existence of a threshold in the NF-κB signaling module. As an example, the switch mechanism for NF-κB activation in B cell receptor (BCR) signaling includes MAGUK protein 1 (CARMA1, CARD11), TAK1 (MAP3K7), and IKKβ (Shinohara et al. 2014).

NF-κB activation and nuclear translocation can proceed either through the classical/canonical pathway, that is a rapid and transient response of stimuli involving mainly RelA/p50, or the alternative/noncanonical NF-κB pathway, that involves slow activation of the RelB/p52 heterodimer leading to prolonged activation of NF-κB target genes (Sanz et al. 2010a) (Figs. 1 and 2). These pathways require different IKK complexes, activate different NF-κB complexes, and may have different target genes. While many stimuli have been shown to activate the canonical NF-κB pathway, the list of noncanonical NF-κB pathway activators is more limited (Poveda et al. 2013).
NF-κB Family, Fig. 2

Temporal pattern profile of TWEAK-induced canonical and noncanonical NF-κB pathway activation in renal proximal tubular epithelial cells. TWEAK is one of a handful of TNF superfamily cytokines that activates both the canonical NF-κB pathway, leading to early transient nuclear translocation of RelA/p50, and the noncanonical NF-κB pathway, leading to delayed nuclear translocation of RelB/p52

Canonical pathway: The classical NF-κB pathway is triggered by most of the stimuli that activate NF-κB. The activated IKK complex IKKα, IKKβ, and NEMO phosphorylates two specific serines near the N terminus of IκBα to trigger its ubiquitin-dependent degradation by the 26S proteasome, allowing nuclear migration of RelA/p50 and other NF-κB dimers (Haas 2009).

Noncanonical pathway: The alternative pathway results in nuclear translocation of the heterodimer RelB/p52 leading to prolonged activation of NF-κB target genes (Senftleben et al. 2001). Only a small number of stimuli are known to activate NF-κB via this pathway, including TNF superfamily members such as TWEAK, but also lymphotoxin-α, BAFF, or RANKL (Sanz et al. 2010b). This pathway requires IKKα phosphorylation by NF-κB-inducing kinase (NIK, MAP3K14), a serine/threonine kinase that binds to TRAF2. Activation of the noncanonical NF-κB pathway involves degradation of an inhibitory protein, TNF receptor-associated factor 3 (TRAF3). The deubiquitinase OTUD7B is a pivotal regulator of signal-induced noncanonical NF-κB activation through deubiquitination and stabilization of TRAF3 (Hu et al. 2013). IKKα phosphorylates p100 leading its polyubiquitination and promoting the proteasomal processing to p52, freeing the active p52/RelB dimers that migrate to the nucleus (Senftleben et al. 2001).

The noncanonical IKKε (IKKi) is a serine/threonine kinase inducible by inflammatory mediators that activates IRF-7; phosphorylates IκBα, NF-κB p65, and c-Rel; and is required for activation of an NF-κB complex containing p52 and p65 (Wietek et al. 2006; Harris et al. 2006). However, mice bearing a deletion of the IKKε gene activate NF-κB normally in response to LPS.

Hybrid pathways: The hybrid pathway of NF-κB activation requires the contribution of both pathways: the NF-κB complex is generated by the alternative pathway and is activated by the classical pathway (Sanz et al. 2010a). MAP3K14 may also stimulate the canonical NF-kB pathway.

Finalization of NF-κB Activation

NF-κB activation is regulated by negative feedback loops, which control the duration of NF-κB nuclear localization in response to a stimulus. Negative feedback mechanisms include NF-κB-dependent induction of IκBα, A20, and Cezanne. Newly formed IκBα sequesters NF-κB subunits and terminates transcriptional activity unless a persistent activation signal is present. Deubiquitinating enzymes CYLD (cylindromatosis gene), A20, and Cezanne induced by proinflammatory signaling can block IKK activation by removing polyubiquitin chains (Van der Heiden et al. 2010). Inactivation of DNA-bound NF-κB requires copper metabolism Murr1 domain-containing (COMMD) proteins, that regulate the ubiquitination pathway, and acts in conjunction with CCDC22 to direct the degradation of IκB proteins (Starokadomskyy et al. 2013).

The “NF-κB-p62-mitophagy” pathway is a macrophage-intrinsic regulatory loop through which NF-κB restrains its own inflammation-promoting activity and orchestrates a self-limiting host response that maintains homeostasis and favors tissue repair by restraining NLRP3-inflammasome activation (Zhong et al. 2016).

Target Genes

NF-κB complexes regulate the transcription of multiple genes related to inflammation, immunity, apoptosis, cell proliferation, and differentiation. At http://people.bu.edu/gilmore/nf-kb/ the reader can find updated lists of NF-κB gene targets classified by function as cytokines/chemokines and their modulators, immunoreceptors proteins involved in antigen presentation, cell adhesion molecules, acute phase proteins, stress response genes, cell-surface receptors, regulators of apoptosis, growth factors, ligands and their modulators, early response genes, transcription factors and regulators, viruses, enzymes, and others.

While NF-κB frequently promotes gene transcription, it may also function as a repressor of gene expression. Thus, anti-inflammatory cytokines may induce the synthesis of nuclear-located atypical IκB proteins, which bind to DNA-bound NF-κB dimers and repress transcription of inflammatory genes (Ghosh and Hayden 2008). Additional mechanism involves competition of RelA with co-activators of transcription, posttranslational modifications of RelA, and posttranslational modification of histones near the NF-κB target genes (Sanz et al. 2010a).

No clear-cut differences in DNA-binding sequences have been observed for the different NF-κB complexes, and considerable promiscuity is thought to occur.

The Role of NF-κB Signaling in Disease

Studies in knockout mice have revealed specific functions of each NF-κB family proteins in the regulation of disease. Deletion of RelA or IKKβ genes in mice causes embryonic lethality due to excess apoptosis in the liver indicating that their function is indispensable during development (Beg et al. 1995; Li et al. 1999). On the other hand, mice lacking RelB are immunodeficient but develop normally to adulthood (Sha et al. 1995). Mice lacking c-Rel or p52 have defective immune functions (Caamaño et al. 1998).

Dysregulated activation of the NF-κB pathway is involved in the pathogenesis of a number of human diseases. The NF-κB family controls multiple processes, including immunity, inflammation, cell survival, differentiation and proliferation, and regulates cellular responses to stress, hypoxia, stretch, and ischemia. Activation of the NF-κB pathway is involved in the pathogenesis of chronic inflammatory disease, kidney disease, atherosclerosis, infections, neurological diseases, cancer, and aging, among others. Evidence for the involvement of NF-κB in disease often comes from functional studies in experimental cell and animal models as well as descriptive data from animal models and human samples. We will provide some examples of NF-κB involvement in disease processes.

Inflammation

NF-κB is involved in the pathophysiology of autoimmune and inflammatory disorders, such as rheumatoid arthritis, asthma, and others.

NF-κB is activated in the inflamed synovium of rheumatoid arthritis patients as well as in the synovium of animal models in this disease. Intra-articular gene transfer of IKKβ into the joints of normal rats resulted in synovial inflammation, while dominant-negative adenoviral IKKβ construct ameliorated the severity of arthritis. NF-κB “decoy” or RelA antisense oligodeoxynucleotides prevented the development of arthritis in rats (Neurath et al. 1996).

Asthma is characterized by the lung infiltration of inflammatory cells, increased NF-κB, and is evident in biopsies from asthmatic patients (Kumar et al. 2004). Treatment with steroids decreases NF-κB activity in mice, cultured cells (Kumar et al. 2004), and in asthmatic patients as well as reducing the symptoms of the disease.

Kidney Disease and Aging

The role and regulation of NF-κB in kidney disease was recently reviewed and includes functional studies showing improvement of kidney disease outcomes when targeting NF-κB in experimental models (Sanz et al. 2010a). In tubular cells, NFκBiz protein downregulation, as observed in experimental AKI, increases inflammatory responses while protecting from inflammation-induced apoptosis and also prevents klotho downregulation (Poveda et al. 2016). More recently, MAP3K14 activity-deficient aly/aly (MAP3K14 aly/aly) mice are protected from AKI, and this appears to depend on kidney cell MAP3K14 deficiency that limits tubular cell inflammatory responses (Ortiz et al. 2017). Many drugs used in kidney disease target NF-κB, including steroids, calcineurin inhibitors, drugs targeting the renin-angiotensin system, and statins, but no functional studies of therapies specifically targeting NF-κB are available in humans. The recent observation that inflammation downregulates klotho mRNA expression and protein via NF-κB activation provides a link between inflammation, kidney disease, NF-κB, and accelerated aging (Moreno et al. 2011). Klotho is a kidney-secreted hormone with antiaging properties and klotho knockout mice die prematurely from accelerated aging. Indeed, this may represent a wider phenomenon of NF-κB-mediated suppression of cell- or tissue-protective genes, since NF-κB also mediated the inflammation-induced downregulation of the mitochondria biogenesis regulator PGC1α (Ruiz-Andres et al. 2016). In addition, DNA damage drives aging in part through NF-κB activation involving RelA and IKK, and this was prevented by IKK/NF-κB inhibitors (Tilstra et al. 2012).

Cardiovascular Disease

NF-κB has been linked to both cardiovascular health and disease. NF-κB can protect cardiovascular tissues from injury or contribute to pathogenesis depending on the cellular and physiological context.

Atherosclerosis is a chronic lipid-driven inflammatory disease characterized by accumulation of lipids in arterial walls, which can lead to a heart attack or stroke. Recruitment of monocytes and their extravasation into the subendothelial space, a key event in atherogenesis, is regulated by NF-κB. Activated NF-κB has been identified in situ in human atherosclerotic plaques (Collins and Cybulsky 2001).

One consequence of atherosclerosis is tissue ischemia. Ischemia-reperfusion alters oxygen availability leading to NF-κB activation through proinflammatory cytokines and endogenous ligands for TLRs. Blocking NF-κB using pharmacological inhibitors or decoy oligonucleotides can reduce myocardial infarction in animal models. However, in a murine myocardial infarction model NF-κB activation was essential for the protection of cardiomyocytes from apoptosis via induction of cytoprotective genes (Van Der Heiden et al. 2010). This illustrates the “good and evil” aspects of NF-κB.

Human Immunodeficiency Virus (HIV) and Other Infections

Most viruses encode proteins that are capable of activating NF-κB. HIV infection induces NF-κB activation that allows evading the immune response. HIV has two NF-κB binding sites called long terminal repeat (LTR) that are involved in viral transcription. NF-κB activation by viral infection is required for viruses to induce proliferative responses, like expression of cyclin D1, replicate their genetic material, and induce pathogenic responses.

In the response to bacterial infections, the M1 to M2 macrophage reprogramming that develops during LPS tolerance depends on shifting the balance between active p65-p50 and inhibitory p50-p50 NF-κB pathways (Rackov et al. 2016). RelA is essential for stress-induced transcriptional remodeling in the liver and the subsequent activation of the acute phase response, whose functional role includes compartmentalization of local infection, decreasing bacterial infection-induced death (Quinton et al. 2012). Several mutations in NF-κB genes cause immune deficiency. IKBKB mutations encoding IKK2 were recently reported to induce deficiency of innate and acquired immunity characterized by hypogammaglobulinemia or agammaglobulinemia, peripheral blood B cells and T cells almost exclusively of naive phenotype and absent regulatory T cells and γδ T cells (Pannicke et al. 2013).

Neurological Diseases

NF-κB is associated with antiapoptotic as well as proapoptotic mechanisms. Consistent with its role in regulating apoptosis, NF-κB serves as a cell survival role in stressed neurons through the upregulation of antiapoptotic and antioxidant genes. NF-κB activation may also be involved in the initiation of neuritic plaques and neuronal apoptosis during the early phases of Alzheimer’s disease, whereas mature plaque types show mainly reduced NF-κB activity (Kumar et al. 2004).

Cancer

A variety of dysregulations of NF-κB activation has been described in cancer cells and thought to be of pathogenic relevance. NF-kB may have a dual role in oncogenesis. Loss of the tumor-suppressor function of RelA in the early stages of Kras-driven pancreatic neoplastic transformation was associated with a protumorigenic tumor microenvironment. By contrast, in advanced stages of Kras-driven murine pancreatic ductal adenocarcinoma, RelA enhanced tumor progression (Korc 2016). Constitutive NF-κB activation is involved in some forms of cancer, and inhibition of NF-κB abrogates cell proliferation in these tumors (Kumar et al. 2004). Genes encoding RelA, c-Rel, p105/p50, and p100/p52 proteins are located within regions of the genome involved in oncogenic rearrangements or amplifications. Oncogenic fusions between RELA and C11orf95 are frequent in supratentorial ependymomas and result in fusion proteins that are translocated spontaneously to the nucleus to activate NF-κB target genes and rapidly transform neural stem cells (Parker et al. 2014). Mutations that can lead to tumors include those that inactivate IκB proteins as well as amplifications of genes encoding NF-κB. In tumor models, NF-κB is activated in tumor cells in response to chemotherapy, and inhibition of NF-κB by viral expression of IκB leads to enhancement in the apoptotic response of the chemotherapy.

In cancer cells, negative feedback loops are overridden through unclear mechanisms to sustain oncogenic activation of NF-κB signaling. Overexpression of miR-30e* directly represses IκBα expression, while miR-182 directly suppressed cylindromatosis (CYLD), another NF-κB negative regulator, leading to prolonged NF-κB activation in cancer (Song et al. 2012).

NF-κB activation may also contribute to cancer complications. Serum factors from cachectic mice and patients induce Pax7 expression in an NF-κB-dependent manner, and this impairs the regenerative capacity of myogenic cells in the muscle microenvironment to drive muscle wasting in cancer (He et al. 2013).

Therapeutic Targeting of NF-κB

The identification of NF-κB as a key player in the pathogenesis of disease suggests that NF-κB-targeting drugs aimed at blocking NF-κB activity might be effective in the clinic. Suppression of NF-κB activation has potential therapeutic applications. In fact, some well-known commercially available drugs, such as glucocorticoids, nonsteroidal anti-inflammatory drugs, and calcineurin inhibitors, modulate NF-κB activity.

Repression of NF-κB-dependent gene expression is one of the major elements of immunosuppression and anti-inflammation by glucocorticoids. Glucocorticoids induce IκBα synthesis and enhance the cytosolic retention of NF-κB in monocytes and lymphocytes (Yamamoto and Gaynor 2001). However, glucocorticoids block NF-κB activation by different mechanisms in different cell types.

Nonsteroidal anti-inflammatory drugs are used in the treatment of chronic inflammatory disease. Most of them also target NF-κB. Both aspirin and salicylate inhibit NF-κB activation in patients with chronic inflammatory conditions by inhibiting ATP binding to IKKβ.

Cyclosporin A (CsA) and tacrolimus (FK-506) are calcineurin-inhibitor immunosuppressive agents used in organ transplantation to prevent rejection. Both inhibit the NF-κB pathway in lymphocytes by distinct mechanisms: preventing IκBα degradation and translocation of c-Rel from the cytoplasm to the nucleus, respectively (Yamamoto and Gaynor 2001). By contrast, nephrotoxicity is in part mediated by recruitment of NF-κB-mediated inflammatory responses in tubular cells (González-Guerrero et al. 2013).

Proteasome inhibitors may prevent NF-κB activation function by reducing IκB degradation. There are a variety of proteasome inhibitors, some in clinical use, like bortezomib.

Since oxygen radical species promote NF-κB activation, drugs with antioxidant properties may inhibit NF-κB activation.

A variety of other approaches has been used to inhibit NF-κB activation in cell culture or experimental animal models (http://people.bu.edu/gilmore/nf-kb/inhibitors/index.html). These include small molecules, siRNA, oligodeoxynucleotides, degradation-resistant IκBs, peptide-siRNA nanocomplexes targeting specific NF-κB subunits, and other specific NF-κB inhibitors, whose efficacy has been shown in animal models of inflammatory disease. Since NF-κB may have dualistic roles in disease, specific NF-κB inhibition might result in unintended side effects. As an example, NF-κB may promote both cell survival and inflammation in cells stimulated with certain cytokines, such as TNF or TRAIL, and NF-κB inhibition in these circumstances may result both in less secretion of inflammatory mediators and cell death.

Summary

NF-κB is a term used for a family of transcription factors composed of homo- or heterodimeric DNA-binding protein complexes that may be activated in response to a wide variety of stimulus inducing cell stress. NF-κB, in turn, promotes the transcription or repression of a wide array of genes involved in many key cell biology processes. As a result, NF-κB contributes to the pathogenesis of many diseases. Specific NF-κB inhibition is promising in experimental animal models, but experience in humans is limited. By contrast, many commonly used drugs may target NF-κB directly or indirectly as one of several mechanisms of action.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Lara Valiño-Rivas
    • 1
  • Laura Gonzalez-Lafuente
    • 1
  • Ana B. Sanz
    • 2
  • Jonay Poveda
    • 1
  • Alberto Ortiz
    • 2
  • Maria D. Sanchez-Niño
    • 2
  1. 1.IIS-Fundacion Jimenez DiazMadridSpain
  2. 2.IIS-Fundacion Jimenez Diaz and Universidad Autonoma de MadridMadridSpain