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Sevilla L.M.,Institute Biomedicina Of Valencia Consejo Superior Of Investigaciones Cientificas Ibv Csic | Latorre V.,Institute Biomedicina Of Valencia Consejo Superior Of Investigaciones Cientificas Ibv Csic | Latorre V.,University of Manchester | Carceller E.,Institute Biomedicina Of Valencia Consejo Superior Of Investigaciones Cientificas Ibv Csic | And 5 more authors.
Molecular and Cellular Endocrinology | Year: 2015

The glucocorticoid (GC) receptor (GR) and Kruppel-like factor Klf4 are transcription factors that play major roles in skin homeostasis. However, whether these transcription factors cooperate in binding genomic regulatory regions in epidermal keratinocytes was not known. Here, we show that in dexamethasone-treated keratinocytes GR and Klf4 are recruited to genomic regions containing adjacent GR and KLF binding motifs to control transcription of the anti-inflammatory genes Tsc22d3 and Zfp36. GR- and Klf4 loss of function experiments showed total GR but partial Klf4 requirement for full gene induction in response to dexamethasone. In wild type keratinocytes induced to differentiate, GR and Klf4 protein expression increased concomitant with Tsc22d3 and Zfp36 up-regulation. In contrast, GR-deficient cells failed to differentiate or fully induce Klf4, Tsc22d3 and Zfp36 correlating with increased expression of the epithelium-specific Trp63, a known transcriptional repressor of Klf4. The identified transcriptional cooperation between GR and Klf4 may determine cell-type specific regulation and have implications for developing therapies for skin diseases. © 2015 Elsevier Ireland Ltd.


PubMed | Queen's University of Belfast, University of Valencia, University of Oslo and Institute Biomedicina Of Valencia Consejo Superior Of Investigaciones Cientificas Ibv Csic
Type: | Journal: Molecular and cellular endocrinology | Year: 2015

The glucocorticoid (GC) receptor (GR) and Kruppel-like factor Klf4 are transcription factors that play major roles in skin homeostasis. However, whether these transcription factors cooperate in binding genomic regulatory regions in epidermal keratinocytes was not known. Here, we show that in dexamethasone-treated keratinocytes GR and Klf4 are recruited to genomic regions containing adjacent GR and KLF binding motifs to control transcription of the anti-inflammatory genes Tsc22d3 and Zfp36. GR- and Klf4 loss of function experiments showed total GR but partial Klf4 requirement for full gene induction in response to dexamethasone. In wild type keratinocytes induced to differentiate, GR and Klf4 protein expression increased concomitant with Tsc22d3 and Zfp36 up-regulation. In contrast, GR-deficient cells failed to differentiate or fully induce Klf4, Tsc22d3 and Zfp36 correlating with increased expression of the epithelium-specific Trp63, a known transcriptional repressor of Klf4. The identified transcriptional cooperation between GR and Klf4 may determine cell-type specific regulation and have implications for developing therapies for skin diseases.


Bem A.E.,Wageningen University | Velikova N.,Institute Biomedicina Of Valencia Consejo Superior Of Investigaciones Cientificas Ibv Csic | Pellicer M.T.,Ferrer HealthTech | Baarlen P.V.,Wageningen University | And 3 more authors.
ACS Chemical Biology | Year: 2015

Bacterial histidine kinases (HKs) are promising targets for novel antibacterials. Bacterial HKs are part of bacterial two-component systems (TCSs), the main signal transduction pathways in bacteria, regulating various processes including virulence, secretion systems and antibiotic resistance. In this review, we discuss the biological importance of TCSs and bacterial HKs for the discovery of novel antibacterials, as well as published TCS and HK inhibitors that can be used as a starting point for structure-based approaches to develop novel antibacterials. © 2014 American Chemical Society.


PubMed | University of Perugia, Institute Biomedicina Of Valencia Consejo Superior Of Investigaciones Cientificas Ibv Csic and Inflammation Research Center
Type: | Journal: Scientific reports | Year: 2016

Psoriasis vulgaris is a chronic inflammatory skin disease affecting millions of people. Its pathophysiology is complex and involves a skin compartment with epidermal and immune cells which produce cytokines, e.g. belonging to the IL-23-Th17-cell axis. Glucocorticoids (GCs) are the most common therapeutics used in cutaneous inflammatory disorders and GC-induced leucine zipper (GILZ) has emerged as a mediator of GCs due to its anti-inflammatory actions, theoretically lacking GC side-effects. We evaluated whether GILZ may provide a better therapeutic index in comparison to GCs during the onset and progression of psoriasis by generating and characterizing a mouse model with generalized overexpression of this protein (GILZ-Tg mice) and the imiquimod (IMQ) psoriasis model. Unexpectedly, in GILZ-Tg mice, the severity of IMQ-induced psoriasis-like skin lesions as well as induction of cytokines commonly up-regulated in human psoriasis (Il-17, Il-22, Il-23, Il-6, S100a8/a9, and Stat3) was significantly more pronounced relative to GILZ-Wt mice. The increased susceptibility to IMQ-induced psoriasis of GILZ-Tg mice was significantly associated with skin-specific over-activation of TGF-1-mediated signaling via SMAD2/3. Our findings demonstrate that GILZ may behave as pro-inflammatory protein in certain tissues and that, similar to prolonged GC therapy, GILZ as an alternative treatment for psoriasis may also have adverse effects.


Marin I.,Institute Biomedicina Of Valencia Consejo Superior Of Investigaciones Cientificas Ibv Csic
PLoS ONE | Year: 2013

HECT ubiquitin ligases are key components of the ubiquitin-proteasome system, which is present in all eukaryotes. In this study, the patterns of emergence of HECT genes in plants are described. Phylogenetic and structural data indicate that viridiplantae have six main HECT subfamilies, which arose before the split that separated green algae from the rest of plants. It is estimated that the common ancestor of all plants contained seven HECT genes. Contrary to what happened in animals, the number of HECT genes has been kept quite constant in all lineages, both in chlorophyta and streptophyta, although evolutionary recent duplications are found in some species. Several of the genes found in plants may have originated very early in eukaryotic evolution, given that they have clear similarities, both in sequence and structure, to animal genes. Finally, in Arabidopsis thaliana, we found significant correlations in the expression patterns of HECT genes and some ancient, broadly expressed genes that belong to a different ubiquitin ligase family, called RBR. These results are discussed in the context of the evolution of the gene families required for ubiquitination in plants. © 2013 Ignacio Marín.


Montoro-Garcia S.,University of Murcia | Gil-Ortiz F.,Institute Biomedicina Of Valencia Consejo Superior Of Investigaciones Cientificas Ibv Csic | Garcia-Carmona F.,University of Murcia | Polo L.M.,Institute Biomedicina Of Valencia Consejo Superior Of Investigaciones Cientificas Ibv Csic | And 2 more authors.
Biochemical Journal | Year: 2011

Organophosphorus insecticides and nerve agents irreversibly inhibit serine hydrolase superfamily enzymes. One enzyme of this superfamily, the industrially important (for β-lactam antibiotic synthesis) AXE/CAH (acetyl xylan esterase/cephalosporin acetyl hydrolase) from the biotechnologically valuable organism Bacillus pumilus, exhibits low sensitivity to the organophosphate paraoxon (diethyl-p-nitrophenyl phosphate, also called paraoxonethyl), reflected in a high Ki for it (∼5 mM) and in a slow formation (t 1/2∼1 min) of the covalent adduct of the enzyme and for DEP (E-DEP, enzyme-diethyl phosphate, i.e. enzyme-paraoxon). The crystal structure of the E-DEP complex determined at 2.7 Å resolution (1 Å=0.1 nm) reveals strain in the active Ser181-bound organophosphate as a likely cause for the limited paraoxon sensitivity. The strain results from active-site-size limitation imposed by bulky conserved aromatic residues that may exclude as substrates esters having acyl groups larger than acetate. Interestingly, in the doughnut-like homohexamer of the enzyme, the six active sites are confined within a central chamber formed between two 60°-staggered trimers. The exclusive access to this chamber through a hole around the three-fold axis possibly limits the size of the xylan natural substrates. The enzyme provides a rigid scaffold for catalysis, as reflected in the lack of movement associated with paraoxon adduct formation, as revealed by comparing this adduct structure with that also determined in the present study at 1.9 Å resolution for the paraoxon-free enzyme. © The Authors Journal compilation © 2011 Biochemical Society.


PubMed | Institute Biomedicina Of Valencia Consejo Superior Of Investigaciones Cientificas Ibv Csic
Type: Journal Article | Journal: The Journal of investigative dermatology | Year: 2013

The glucocorticoid (GC) receptor (GR) mediates the effects of physiological and pharmacological GC ligands and has a major role in cutaneous pathophysiology. To dissect the epithelial versus mesenchymal contribution of GR in developing and adult skin, we generated mice with keratinocyte-restricted GR inactivation (GR epidermal knockout or GR(EKO) mice). Developing and early postnatal GR(EKO) mice exhibited impaired epidermal barrier formation, abnormal keratinocyte differentiation, hyperproliferation, and stratum corneum (SC) fragility. At birth, GR(EKO) epidermis showed altered levels of epidermal differentiation complex genes, proteases and protease inhibitors which participate in SC maintenance, and innate immunity genes. Many upregulated genes, including S100a8/a9 and Tslp, also have increased expression in inflammatory skin diseases. Infiltration of macrophages and degranulating mast cells were observed in newborn GR(EKO) skin, hallmarks of atopic dermatitis. In addition to increased extracellular signal-regulated kinase activation, GR(EKO) newborn and adult epidermis had increased levels of phosphorylated signal transducer and activator of transcription 3, a feature of psoriasis. Although adult GR(EKO) epidermis had a mild phenotype of increased proliferation, perturbation of skin homeostasis with detergent or phorbol ester triggered an exaggerated proliferative and hyperkeratotic response relative to wild type. Together, our results show that epidermal loss of GR provokes skin barrier defects and cutaneous inflammation.


PubMed | Institute Biomedicina Of Valencia Consejo Superior Of Investigaciones Cientificas Ibv Csic
Type: Journal Article | Journal: The Journal of investigative dermatology | Year: 2013

We recently demonstrated that mice lacking the epidermal glucocorticoid (GC) receptor (GR) (GR epidermal knockout (GR(EKO)) mice) have developmental defects and sensitivity to epidermal challenge in adulthood. We examined the susceptibility of GR(EKO) mice to skin chemical carcinogenesis. GR(EKO) mice treated with a low dose of 12-dimethylbenz(a) anthracene (DMBA) followed by phorbol 12-myristate 13-acetate (PMA) promotion exhibited earlier papilloma formation with higher incidence and multiplicity relative to control littermates (CO). Augmented proliferation and inflammation and defective differentiation of GR(EKO) keratinocytes contributed to the phenotype, likely through increased AKT and STAT3 (signal transducer and activator of transcription 3) activities. GR(EKO) tumors exhibited signs of early malignization, including delocalized expression of laminin A, dermal invasion of keratin 5 (K5)-positive cells, K13 expression, and focal loss of E-cadherin. Cultured GR(EKO) keratinocytes were spindle like, with loss of E-cadherin and upregulation of smooth muscle actin (SMA) and Snail, suggesting partial epithelial-mesenchymal transition. A high DMBA dose followed by PMA promotion generated sebaceous adenomas and melanocytic foci in GR(EKO) and CO. Importantly, the number, growth kinetics, and extent of both tumor types increased in GR(EKO) mice, suggesting that in addition to regulating tumorigenesis from epidermal lineages, GR in keratinocytes is important for cross-talk with other skin cells. Altogether, our data reinforce the importance of GR in the pathogenesis of skin cancer.

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