Paloma Perez

Spanish National Research Council | CSIC · Institute of Biomedicine of Valencia

Glucocorticoids (GCs) exert potent antiproliferative and anti‐inflammatory properties, explaining their therapeutic efficacy for skin diseases. GCs act by binding to the GC receptor (GR) and the mineralocorticoid receptor (MR), co‐expressed in classical and non‐classical targets including keratinocytes. Using knockout mice, we previously demonstrat...

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptio...

The Mineralocorticoid Receptor (MR or NR3C2) is expressed in all cell types of the different skin compartments and can be bound and activated by glucocorticoids (GCs) with higher affinity than its closely related glucocorticoid (GC) receptor (GR or NR3C1). As both corticosteroid receptors co‐express in skin, and considering the therapeutic relevanc...

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptio...

Endogenous glucocorticoids (GCs) are steroid hormones that signal in virtually all cell types to modulate tissue homeostasis throughout life. Also, synthetic GC derivatives (pharmacological GCs) constitute the first-line treatment in many chronic inflammatory conditions with unquestionable therapeutic benefits despite the associated adverse effects...

Nuclear receptors (NRs) are a superfamily of ligand-activated transcription factors that act as biological sensors and use a combination of mechanisms to modulate positively and negatively gene expression in a spatial and temporal manner. The highly orchestrated biological actions of several NRs influence the proliferation, differentiation, and apo...

Glucocorticoid (GC) actions are mediated through two closely related ligand-dependent transcription factors, the GC receptor (GR) and the mineralocorticoid receptor (MR). Given the wide and effective use of GCs to combat skin inflammatory diseases, it is important to understand the relative contribution of these receptors to the transcriptional res...

The endogenous increased production of glucocorticoids (GCs) in the skin of the elderly population contributes to age-related defects strikingly similar to those occurring after pharmacological treatments with GCs. GCs act through the ligand-dependent transcription factors GC receptor (GR) and mineralocorticoid receptor (MR). We demonstrated that e...

Psoriasis is a prevalent chronic inflammatory human disease initiated by impaired function of immune cells and epidermal keratinocytes, resulting in increased cytokine production and hyperproliferation, leading to skin lesions. Overproduction of Th1- and Th17-cytokines including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-23...

Nuclear receptors are transcription factors that play critical roles in development, homeostasis and metabolism in all multicellular organisms. An important family of nuclear receptors comprises those members that respond to steroid hormones, and which is subdivided in turn into estrogen receptor (ER) isoforms α and β (NR3A1 and A2, respectively),...

Keywords: angiogenesis, antithrombin, cardiac surgery, cardiopulmonary bypass, dexamethasone, endothelial function

The nuclear hormone receptor (NR) superfamily comprises approximately 50 evolutionarily conserved proteins that play major roles in gene regulation by prototypically acting as ligand-dependent transcription factors. Besides their central role in physiology, NRs have been largely used as therapeutic drug targets in many chronic inflammatory conditio...

Endogenous and synthetic glucocorticoids (GCs) regulate epidermal development and combat skin inflammatory diseases. GC actions can be mediated through the GC receptor (GR) and/or the mineralocorticoid receptor (MR), highly homologous ligand-activated transcription factors. While the role of GR as a potent anti-inflammatory mediator is well known,...

Primary aldosteronism (PA) is a disease characterized by high aldosterone levels caused by benign adrenal tumors being the most frequent cause of secondary hypertension. Aldosterone plays vital physiological roles through the mineralocorticoid receptor (MR) but in certain cell types, it can also activate the glucocorticoid (GC) receptor (GR). Both...

p23 is a small acidic protein with intrinsic molecular chaperone activity. It is best known as a co-chaperone of the major cytosolic molecular chaperone Hsp90. p23 binds the N-terminus of Hsp90 and stabilizes the ATP-bound and N-terminally closed Hsp90 dimer. It is in this configuration that many Hsp90 clients are most stably bound. Considering the...

Glucocorticoids (GC) are the primary steroids that regulate inflammation and have been exploited therapeutically in inflammatory skin diseases. Despite the broad-spectrum therapeutic use of GC the biochemical rationale for locally treating inflammatory skin conditions is poorly understood, as systemic GC production remains largely functional in the...

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 an...

Glucocorticoids (GCs) regulate skin homeostasis and combat cutaneous inflammatory diseases, however, adverse effects of chronic GC treatments limit their therapeutic use. GCs bind and activate the GC receptor (GR) and the mineralocorticoid receptor (MR), transcription factors that recognize identical hormone responsive elements (HREs). Whether epid...

The importance of hormonal regulation in skin is evidenced by numerous endocrine abnormalities with cutaneous manifestations, including disorders of the epidermal barrier and hair (1, s1). Hormone action is mediated by nuclear receptor superfamily members, ligand-activated transcription factors that integrate multiple cellular processes, including...

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 recru...

We recently demonstrated that mice lacking epidermal glucocorticoid (GC) receptor (GR) (GR epidermal knock-out or 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 DMBA followed by PMA p...

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) m...

Delayed wound healing is one of the most common secondary adverse effects associated to the therapeutic use of glucocorticoid (GC) analogs, which act through the ligand-dependent transcription factor GC-receptor (GR). GR function is exerted through DNA-binding-dependent and -independent mechanisms, classically referred to as transactivation (TA) an...

Specificity of TNF-α immunostaining. The dorsal skin of adult WT mice was topically treated with either vehicle (untreated) or PMA (8 µg) for 2 weeks, and immunostaining using a secondary antibody only (left) or TNF-α antibody (right) was performed. Representative images of three independent experiments are shown. (TIF)

Alterations in nuclear factor kappaB (NFκB) signaling have been related with several diseases and importantly also with cancer. Different animal models with increased or diminished NFκB signaling have shown that NFκB subunits and their regulators are relevant to the pathophysiology of different organs and tissues. In particular, both the deletion o...

Glucocorticoids (GCs) exert their biological and therapeutical actions through the GC receptor (GR), a ligand-dependent transcription factor. Synthetic GC derivatives are widely prescribed for treating numerous cutaneous inflammatory and immune diseases due to their great efficacy. However, chronic treatment with GCs produces adverse side-effects i...

Glucocorticoids (GCs) exert their biological and therapeutical actions through the GC receptor (GR), a ligand-dependent transcription factor. Synthetic GC derivatives are widely prescribed for treating numerous cutaneous inflammatory and immune diseases due to their great efficacy. However, chronic treatment with GCs produces adverse side-effects i...

We have previously shown that the glucocorticoid receptor (GR) is required for skin homeostasis and epidermal barrier competence. To understand the transcriptional program by which GR regulates skin development, we performed a microarray analysis using the skin of GR(-/-) and GR(+/+) mice of embryonic d 18.5 and identified 442 differentially expres...

IKKbeta is a subunit of the IkappaB kinase (IKK) complex required for NF-kappaB activation in response to pro-inflammatory signals. NF-kappaB regulates the expression of many genes involved in inflammation, immunity, and apoptosis, and also controls cell proliferation and differentiation in different tissues; however, its function in skin physiopat...

The glucocorticoid receptor (GR) plays a crucial role in epidermal morphogenesis during embryonic development, as demonstrated by analyzing genetically modified mouse models of GR gain- and loss-of-function. Eyelid formation constitutes a useful model to study epithelial development, as it requires coordinated regulation of keratinocyte proliferati...

Glucocorticoids (GCs) play a key role in skin homeostasis and stress responses acting through the GC receptor (GR), which modulates gene expression by DNA binding-dependent (transactivation) and -independent (transrepression) mechanisms. To delineate which mechanisms underlie the beneficial and adverse effects mediated by GR in epidermis and other...

To investigate the contribution of the glucocorticoid receptor (GR) in skin development and the mechanisms underlying this function, we have analyzed two mouse models in which GR has been functionally inactivated: the knockout GR(-/-) mice and the dimerization mutant GR(dim/dim) that mediates defective DNA binding-dependent transcription. Because G...

Despite that glucocorticoids (GCs), acting through the glucocorticoid receptor (GR) exert a pivotal role in skin physiopathology, specific genes regulated by GR in this tissue are largely unknown. We have used a transgenic mouse model overexpressing GR in epidermal basal cells and outer root sheath (ORS) of the hair follicle (HF) under the control...

The regulatory subunit IKKgamma/NEMO is crucial for skin development and function and although devoid of kinase activity, loss of IKKgamma function completely abolishes the activation of NF-kappaB by all pro-inflammatory cytokines. To inhibit the IkappaB kinase (IKK) complex in keratinocytes, we have used a dominant negative approach by generating...

Hypohidrotic ectodermal dysplasia is a human syndrome defined by maldevelopment of one or more ectodermal-derived tissues, including the epidermis and cutaneous appendices, teeth, and exocrine glands. The molecular bases of this pathology converge in a dysfunction of the transcription factor nuclear factor of the kappa-enhancer in B cells (NF-kappa...

Platelet-derived growth factor (PDGF) ligand and receptors (PDGF-R) activate smooth muscle cell (SMC) proliferation, a key event during vascular obstructive disease. The PDGF-R tyrosine kinase inhibitor STI571 attenuates SMC proliferation and experimental neointimal thickening. Here, we investigated the molecular mechanisms underlying STI571-depend...

The skin-targeted overexpression of the glucocorticoid receptor (GR) in transgenic mice dramatically impairs the inflammatory responses to tumor promoter agents and suppresses skin tumor development. The antiinflammatory, rapid effects of corticosteroids are partially exerted through interference of GR with the phosphatidylinositol 3-kinase (PI3K)/...

Excessive proliferation of immune cells and vascular smooth myocytes (VSMCs) contributes to atherosclerosis. We have previously shown that whole-body inactivation of the growth suppressor p27 exacerbates atherosclerosis in apolipoprotein E-null mice (apoE-/-), and this correlated with increased proliferation of arterial macrophages and VSMCs. In th...

The functions of p107 and p130, members of the retinoblastoma family, include the control of cell cycle progression and differentiation in several tissues. Our previous studies suggested a role for p107 and p130 in keratinocyte differentiation in vitro. We now extend these data using knockout animal models. We found impaired terminal differentiatio...

Glucocorticoids are effective inhibitors of epidermal proliferation and skin tumorigenesis. Glucocorticoids affect cellular functions via glucocorticoid receptor (GR), a well-known transcription factor. Recently, we generated skin-targeted transgenic mice overexpressing GR under control of the keratin5 promoter (K5-GR mice). To test the hypothesis...

Both the diversity and the precisely regulated tissue- and differentiation-specific expression patterns of keratins suggest that these proteins have specific functions in epithelia besides their well known maintenance of cell integrity. In the search for these specific functions, our previous results have demonstrated that the expression of K10, a...

Glucocorticoid hormones act through the glucocorticoid receptor (GR) and they affect almost all physiological systems in the organism. We have previously reported that transgenic mice overexpressing GR under the control of the keratin k5 promoter (K5-GR mice) display severe phenotypic alterations in the epidermis and other ectoderm derivatives (Per...

We sought to determine the relative importance of aging and hypercholesterolemia on atherosclerosis. Although plasma cholesterol levels increased similarly in young and old rabbits fed an atherogenic diet for 2 months, aortic atherosclerotic lesions were more prominent in young animals. This finding was associated with an age-dependent reduction in...

Retinoic acid (RA) induces neural differentiation of SH-SY5Y neuroblastoma cells. We show that the mRNA levels of the differentiation-inhibiting basic helix-loop-helix transcription factors ID1,ID2, and ID3 are down-regulated during RA-induced differentiation of SH-SY5Y cells. The levels of ID proteins decreased in parallel to the observed transcri...

The epidermis is a model particularly well suited to the study of cell proliferation and differentiation, and of alterations of these processes such as carcinogenesis. Compartmentalization exists in this tissue, with the proliferative, less differentiated cells confined to the basal layer and the terminally differentiating, non-proliferative cells...

The mouse skin carcinogenesis protocol is a unique model for understanding the molecular events leading to oncogenic transformation. Mutations in the Ha-ras gene, and the presence of functional cyclin D1 and the EGF receptor, have proven to be important in this system. However, the signal transduction pathways connecting these elements during mouse...

Glucocorticoids (GCs) are potent inhibitors of epidermal proliferation and effective anti-inflammatory compounds, which make them the drug of choice for a wide range of inflammatory and hyperproliferative skin disorders. GC action is mediated via the glucocorticoid receptor (GR). To study the role of GR in skin development and the molecular mechani...

The skin constitutes a primary target for stimuli such as ultraviolet (UV) radiation and tumor promoters, leading to both inflammatory and altered proliferative responses. Since the nuclear factor kappaB (NF-kappaB) family of transcription factors plays a major role in these biological processes, we sought to elucidate its expression in newborn mou...

To elucidate the possible role of NF-kappaB in mouse skin carcinogenesis we studied the expression of p50 (NF-kappaB1), p52 (NF-kappaB2), p65 (RelA) and IkappaB-alpha inhibitor as well as kappaB-binding activity in adult SENCAR mouse skin, skin papillomas, and squamous cell carcinomas (SCC) generated by a two-stage carcinogenesis protocol. We found...

We have previously shown that transgenic mice expressing the oncoprotein v-Rel under the control of a T cell-specific promoter develop T cell lymphomas. Tumor formation was correlated with the presence of p50/v-Rel and v-Rel/v-Rel nuclear kappaB-binding activity. Since experimental evidence has led to the suggestion of a potential tumor suppressor...

We have previously shown that transgenic mice expressing the oncoprotein v-Rel under the control of a T cell–specific promoter develop T cell lymphomas. Tumor formation was correlated with the presence of p50/v-Rel and v-Rel/v-Rel nuclear κB-binding activity. Since experimental evidence has led to the suggestion of a potential tumor suppressor acti...

The MAL gene encodes a proteolipid protein displaying a cell type-specific pattern of expression, including T lymphocytes, myelin-forming cells, and epithelial renal MDCK cells, which has been recently identified as a component of detergent-insoluble membranes known to be enriched in glycolipids and cholesterol. Sequence alignment revealed a high d...

Previous studies have indicated that Bcl-3 interacts through its ankyrin repeats with the transcriptional factors NF-kappaB1 (p50) and NF-kappaB2 (p52), affecting their biological activities. To further investigate the role of Bcl-3 in vivo and its association with the NF-kappaB proteins, we have generated transgenic mice constitutively expressing...

RelA (p65) is one of the strongest activators of the Rel/NF-kappa B family. As a first step to elucidate the mechanisms that regulate its activity in vivo, we have generated transgenic mice overexpressing RelA in the thymus. Although the levels of RelA were significantly increased in thymocytes of transgenic mice, the overall NF-kappa B-binding act...

Basal and stimulated activity of the c-fos promoter is reduced by triiodothyronine (T3) and retinoic acid (RA) in GH1 cells. We examined the influence of these ligands on the activity of reporter constructs containing the AP-1 site, the serum response element (SRE) and the cyclic AMP responsive element (CRE) of the c-fos promoter under control of a...

Incubation with 1 nM triiodothyronine (T3) decreased cycloheximide-induced c-fos mRNA levels and the mRNA response to the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA; 100 nM) or to forskolin (15 microM). T3 also reduced the abundance of nuclear proteins that bind to an AP-1 binding site and the levels of c-Fos protein, as determined b...

Incubation of pituitary GH1 cells with N'-methylnicotinamide, nicotinamide and 3-acetylpyridine which inhibit nuclear ADP-ribosylation and/or the cellular concentration of its substrate NAD+ reduced the amount of nuclear thyroid hormone receptors in a time- and dose-dependent manner without altering the affinity of the receptors for the hormone. A...

Retinoic acid produced a time and dose-dependent depletion of thyroid hormone receptors in GH1 cells without modifying their affinity for triiodothyronine (T3). A maximal decrease (50-70%) was obtained after 24-48 h incubation with 5-10 microM retinoic acid. Treatment with 0.8 nM T3 for 24 h caused a similar reduction and did not potentiate the dec...