Natalia A Riobo-Del Galdo

Natalia A Riobo-Del Galdo
University of Leeds · School of Molecular and Cellular Biology

PhD

About

80
Publications
7,372
Reads
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4,378
Citations
Additional affiliations
October 2019 - present
University of Leeds
Position
  • Professor (Associate)
September 2015 - September 2019
University of Leeds
Position
  • Fellow
January 2015 - July 2015
Thomas Jefferson University
Position
  • Professor (Associate)

Publications

Publications (80)
Article
Full-text available
Chloride intracellular channel 4 (CLIC4) is a recently discovered driver of fibroblast activation in Scleroderma (SSc) and cancer-associated fibroblasts (CAF). CLIC4 expression and activity are regulated by TGF-β signalling through the SMAD3 transcription factor. In view of the aberrant activation of canonical Wnt-3a and Hedgehog (Hh) signalling in...
Article
Full-text available
The Hedgehog (Hh) receptor PTCH1 and the integral membrane protein 2A (ITM2A) inhibit autophagy by reducing autolysosome formation. In this study, we demonstrate that ITM2A physically interacts with PTCH1; however, the two proteins inhibit autophagic flux independently, since silencing of ITM2A did not prevent the accumulation of LC3BII and p62 in...
Article
Background and Aim: Glioblastoma is the most lethal brain tumor. No effective curative treatment is available yet, and it is treated by surgery, temozolomide (TMZ), and radiotherapy, with an average overall survival of around 15 months. Inhibitors of histone deacetylases (HDACs) are being explored against a variety of tumors, including glioblastoma...
Preprint
Chloride intracellular channel 4 (CLIC4) is a recently discovered driver of fibroblast activation in Scleroderma (SSc) and cancer-associated fibroblasts. CLIC4 expression and activity are regulated by TGF-beta signalling through the SMAD3 transcription factor. In view of the aberrant activation of canonical Wnt and Hedgehog (Hh) signalling in fibro...
Article
Full-text available
Glioblastoma multiforme, the most common type of malignant brain tumor as well as the most aggressive one, lacks an effective therapy. Glioblastoma presents overexpression of mesenchymal markers Snail, Slug, and N-Cadherin and of the autophagic marker p62. Glioblastoma cell lines also present increased autophagy, overexpression of mesenchymal marke...
Article
Full-text available
Mammalian Hedgehog (HH) signalling pathway plays an essential role in tissue homeostasis and its deregulation is linked to rheumatological disorders. UBR5 is the mammalian homologue of the E3 ubiquitin-protein ligase Hyd, a negative regulator of the Hh-pathway in Drosophila . To investigate a possible role of UBR5 in regulation of the musculoskelet...
Article
Full-text available
Objectives Systemic sclerosis (SSc) is characterised by tissue fibrosis of the major organs of the body including the skin, lungs and heart. We have previously reported that the lncRNA HOTAIR plays a central role in the activation of SSc myofibroblasts, the key cellular elements of fibrosis. HOTAIR induces fibroblast activation through H3K27me3-med...
Article
Full-text available
Mammalian Hedgehog (HH) signalling pathway plays an essential role in tissue homeostasis and its deregulation is linked to rheumatological disorders. UBR5 is the mammalian homologue of the E3 ubiquitin-protein ligase Hyd, a negative regulator of the Hh-pathway in Drosophila. To investigate a possible role of UBR5 in regulation of the musculoskeleta...
Article
The canonical Hedgehog (Hh) signalling pathway is essential for vertebrate development and its uncontrolled activation is a common occurrence in human cancers. Hh signalling converges in the modification of a family of transcription factors, GLI1, GLI2 and GLI3, to orchestrate a cell type and context-specific transcriptional response. Despite bindi...
Article
Full-text available
Breast cancer (BC) is the leading cause of cancer-related mortality in women, only followed by lung cancer. Given the importance of BC in public health, it is essential to identify biomarkers to predict prognosis, predetermine drug resistance and provide treatment guidelines that include personalized targeted therapies. The Hedgehog (Hh) signaling...
Article
Full-text available
Activation of the Hedgehog (Hh) pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCC), with loss of function of Patched1 (Ptc1) being the most common genomic lesion. Sporadic BCCs also overexpress desmoglein-2 (Dsg2), a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gor...
Article
Full-text available
Primary cilia are solitary organelles that emanate from the plasma membrane during growth arrest in almost all mammalian cells. The canonical Hedgehog (HH) pathway requires trafficking of the G protein-coupled receptor SMOOTHENED (SMO) and the GLI transcription factors to the primary cilium upon binding of a HH ligand to PATCHED1. However, it is un...
Data
Primary cilia are dispensable for RHOA activation by Sphingosine-1-Phosphate receptors. A. Representative RHOA pulldown assays in WT and Kif3a-/- MEFs serum-starved for 24 h and stimulated with 1 μM S1P for 2 min. B. Densitometric quantification of RHOA-GTP/actin increase in response to S1P in both genotypes. *p < 0.05 vs. t = 0; n = 3. (TIFF)
Data
Sphingosine-1-Phosphate reduces cAMP levels. WT MEFs were serum-starved at sub-confluency for 24 h in the presence or absence of 200 ng/ml PTX before treatment with 20 μM forskolin (FSK) or a combination of FSK and 1 μM S1P for 10 min. Lysates were subjected to cAMP EIA as described by the manufacturer. Bars represent % maximal cAMP production. *p...
Data
Akt phosphorylation in response to S1P is Gi-dependent. WT and Kif3a-/- MEFs were serum-starved for 24 h in the presence or absence of 200 ng/ml PTX or vehicle and then stimulated with 1 μM S1P for 0–10 min. AKT phosphorylation at Ser473 was determined by western blot. (TIFF)
Article
Full-text available
Smoothened (SMO), the central transducer of Hedgehog signaling, is coupled to heterotrimeric Gi proteins in many cell types, including cardiomyocytes. In this study, we report that activation of SMO with Sonic Hedgehog (SHH) or a small agonist, purmorphamine, rapidly causes a prolongation of the action potential duration that is sensitive to a SMO...
Article
Full-text available
The Hedgehog family of morphogens has long been known to utilize, through the 7-transmembrane protein Smoothened (Smo), the heterotrimeric G protein Gi in both canonical and noncanonical forms of signaling. Other G proteins, while not specifically utilized by Smo, may nonetheless provide access to some of the events controlled by it. We reported se...
Data
Few if any stress fibers exist in the absence of transduction. (PDF)
Data
Alkaline phosphatase activity following introduction of Gα13QL depends on the nature of the medium. (DOCX)
Data
Alkaline phosphatase expression as a function of purmorphamine concentration. (DOCX)
Data
Genes exhibiting the greatest -fold increases in transcripts following introduction of SmoA1 and Gα13QL, relative to LacZ, in C3H10T1/2 cells. (DOCX)
Article
The Hedgehog family of morphogens has long been known to utilize, through the 7-transmembrane protein Smoothened (Smo), the heterotrimeric G protein Gi in both canonical and noncanonical forms of signaling. Other G proteins, while not specifically utilized by Smo, may nonetheless provide access to some of the events controlled by it. We reported se...
Article
In addition to playing a role in adhesion, desmoglein 2 (Dsg2) is an important regulator of growth and survival signaling pathways, cell proliferation, migration and invasion, and oncogenesis. While low-level Dsg2 expression is observed in basal keratinocytes and is downregulated in non-healing venous ulcers, overexpression has been observed in bot...
Article
The Hedgehog (Hh) receptor Patched1 (PTCH1) is a well-known tumor suppressor that in its active form represses Smoothened (SMO) activity, inhibits proliferation, and induces apoptosis. The cytoplasmic C-terminal domain (CTD) regulates PTCH1 turnover and nucleates a proapoptotic complex. In this study, it was mechanistically determined that Autophag...
Article
Despite significant advances in the management of colorectal cancer the identification of new prognostic biomarkers continues to be a challenge. Since its initial discovery, the role of the Hedgehog (Hh) signaling pathway in carcinogenesis has been extensively studied. We herein review and comment on the prognostic significance of the Hedgehog sign...
Article
The utilization of heterotrimeric G protein, and in particular those of the Gi, family, by Hedgehogs through Smoothened has become increasingly clear. We describe here a method for evaluating the activity of Smoothened toward G proteins in membranes derived from human embryonic kidney-293 (HEK293) cells. The assay relies on receptor-promoted exchan...
Article
The Ptc-lacZ reporter mice are a highly utilized animal model for studying both normal tissue development and cancer. Identifying cell specific activation of Hedgehog (Hh) signaling is essential to understand the effects of this critical and complex signaling pathway. β-gal detection in tissues can be difficult, with various staining procedures yie...
Article
Full-text available
In this study, we show that the transmembrane glycoprotein Trop-2 is up-regulated in human prostate cancer (PCa) with extracapsular extension (stages pT3/pT4) as compared to organ-confined (stage pT2) PCa. Consistent with this evidence, Trop-2 expression is found to be increased in metastatic prostate tumors of Transgenic Adenocarcinoma of Mouse Pr...
Article
Full-text available
Aberrant activation of Hedgehog (Hh) signaling is causative of BCCs and has been associated with a fraction of SCCs. Desmoglein 2 (Dsg2) is an adhesion protein that is upregulated in many cancers and overexpression of Dsg2 in the epidermis renders mice more susceptible to squamous-derived neoplasia. Here we examined a potential crosstalk between Ds...
Article
Full-text available
Cell-cell adhesion is paramount in providing and maintaining multicellular structure and signal transmission between cells. In the skin, disruption to desmosomal regulated intercellular connectivity may lead to disorders of keratinization and hyperproliferative disease including cancer. Recently we showed transgenic mice overexpressing desmoglein 2...
Article
The Hedgehog (Hh) signaling pathway has received a great deal of attention in the past decade due to its involvement in cancer, angiogenesis, and fibrosis. Several inhibitors of the pathway were developed which target the 7-transmembrane protein Smoothened (Smo), core component of the canonical pathway that controls Gli-dependent transcriptional ac...
Book
The second edition of this volume provides novel protocols for the study of newly discovered function and modifications of components of the Hh pathways. The first few chapters discuss methods for stable delivery of soluble Hh proteins in cell cultures that can be adapted for in vivo studies, and mathematical models for studying Hh proteins gradien...
Article
Full-text available
The Hedgehog (Hh) receptor Patched-1 (PTCH1) opposes the activation of Gli transcription factors and induces cell death through a Gli-independent pathway. Here, we report that the C-terminal domain (CTD) of PTCH1 interacts with and is ubiquitylated on K1413 by the E3 ubiquitin-protein ligase Itchy homolog (Itch), a Nedd4 family member. Itch induces...
Article
Full-text available
During myocardial ischemia, upregulation of the Hedgehog (Hh) pathway promotes neovascularization and increases cardiomyocyte survival. The canonical Hh pathway activates a transcriptional program through the Gli family of transcription factors by derepression of the 7TM protein Smoothened (Smo). The mechanisms linking Smo to Gli are complex and, i...
Article
Introduction: Induction of Sonic Hedgehog (Shh) in the myocardium post myocardial infarction promotes neovascularization and reduces infarct size. Shh signals through the 7-TM protein Smoothened (SMO), which we have found to couple to Gi proteins. Our goal is to investigate the effect of Shh on myocardial excitability and electrical remodeling and...
Article
Full-text available
Smoothened (Smo) is a 7-transmembrane (7-TM) protein essential to the activation of Gli transcription factors (Gli) by Hedgehog morphogens. The structure of Smo implies interactions with heterotrimeric G proteins, yet the degree to which G proteins participate in the actions of Hedgehogs remains controversial. We posit that the G(i) family of G pro...
Article
Full-text available
The notion of noncanonical hedgehog (Hh) signaling in mammals has started to receive support from numerous observations. By noncanonical, we refer to all those cellular and tissue responses to any of the Hh isoforms that are independent of transcriptional changes mediated by the Gli family of transcription factors. In this chapter, we discuss the m...
Article
Full-text available
Hedgehog (Hh) proteins regulate the development of a wide range of metazoan embryonic and adult structures, and disruption of Hh signaling pathways results in various human diseases. Here, we provide a comprehensive review of the signaling pathways regulated by Hh, consolidating data from a diverse array of organisms in a variety of scientific disc...
Article
Full-text available
The vertebrate Hedgehog (Hh) pathway has essential functions during development and tissue homeostasis in normal physiology, and its dysregulation is a common theme in cancer. The Hh ligands (Sonic Hh, Indian Hh, and Desert Hh) bind to the receptors Patched1 and Patched2, resulting in inhibition of their repressive effect on Smoothened (Smo). Smo i...
Article
Full-text available
Smoothened (Smo) is a seven-transmembrane (7-TM) receptor that is essential to most actions of the Hedgehog family of morphogens. We found previously that Smo couples to members of the Gi family of heterotrimeric G proteins, which in some cases are integral although alone insufficient in the activation of Gli transcription factors through Hedgehog...
Article
Full-text available
Evidence supporting the functionality of Smoothened (SMO), an essential transducer in most pathways engaged by Hedgehog (Hh), as a Gi-coupled receptor contrasts with the lack of an apparently consistent requirement for Gi in Hh signal transduction. In the present study, we sought to evaluate the role of SMO-Gi coupling in fibroblast migration induc...
Chapter
The Hedgehog and Wnt signaling pathways play critical roles in patterning, proliferation and survival during embryonic development. Abnormal activation of these pathways in adult organisms is associated with a wide rage of neoplasias. In this chapter we provide a concise description of the two signaling pathways and their role in cancer and discuss...
Article
Full-text available
The Hedgehog (Hh) pathway orchestrates developmental and homeostatic angiogenesis. the three Hh isoforms--Sonic Hedgehog (Shh), Indian Hedgehog (Ihh) and Desert Hedgehog (Dhh)--signal through patched-1 (ptCH1) and Smoothened (SMo), to activate the Gli transcription factors with a characteristic rank of potency (Shh > Ihh > Dhh). To dissect the mech...
Article
Full-text available
Mitochondrial biology appears central to many conditions that progress to death but remains poorly characterized after cardiac arrest. Mitochondrial dysfunction in electron transfer and reactive oxygen species leakage during ischemia may lead to downstream events including mitochondrial protein oxidation, tyrosine nitrosylation, cytochrome c loss,...
Article
Full-text available
The Hedgehog (Hh) family of secreted ligands-composed of Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh)-possesses many roles during embryonic development, adult homeostasis, and cancer. The specific functions of the Hh proteins are intertwined with their requirement as survival factors in Hh-responsive cells. However, studie...
Article
Background: Reperfusion injury post-resuscitation is associated with metabolic dysfunction and free radicals production. It has been hypothesized that mitochondrial permeability changes induced by calcium overload underlies this uncoupling of respiration from ATP synthesis and initiates cytochrome c-dependent apoptotic cascades. Our goal is to eval...
Article
Full-text available
Signalling by Hh (Hedgehog) proteins is among the most actively studied receptor-mediated phenomena relevant to development and post-embryonic homoeostatic events. The impact of signalling by the Hh proteins is profound, and work pertaining to the presentation of these proteins and the pathways engaged by them continues to yield unique insights int...
Article
Full-text available
Activation of protein kinase Cdelta (PKCdelta), a member of the novel PKC family, leads to apoptosis in several cell types. Although the molecular bases of PKCdelta activation are being unfolded, limited information is available on the mechanisms that control its expression. Here, we report that in prostate cancer cells PKCdelta is tightly regulate...
Article
Full-text available
The mechanisms by which the activation of Smoothened (Smo), a protein essential to the actions of the Hedgehog family of secreted proteins, is translated into signals that converge on the Gli transcription factors are not fully understood. The seven-transmembrane structure of Smo has long implied the utilization of heterotrimeric GTP-binding regula...
Article
Full-text available
Hedgehog (HH) signaling regulates a diversity of processes involved in developmental patterning, stem cell growth and maintenance, and cancer etiology. Despite its biological importance, the HH signal transduction pathway remains largely mysterious. Our past understanding of the HH pathway signaling components and mechanisms came from groundbreakin...
Article
Full-text available
Hedgehogs (Hhs) are key signaling regulators of stem cell maintenance and tissue patterning in embryos, and activating mutations in the pathway that increase Gli transcriptional activity are causal in a diversity of cancers. Here, we report that phosphoinositide 3-kinase (PI3-kinase)-dependent Akt activation is essential for Sonic Hedgehog (Shh) si...
Article
Full-text available
One third of all lethal cancers are associated with excessive activation of the Hedgehog (HH) pathway by mutations of its signaling components or by increased responsiveness of cells to the HH ligand. HH signaling through the GLI transcription factors leads to increased cell proliferation by up-regulation of the extracellular regulated kinase (ERK)...
Article
Much regarding the engagement of the G(12) family of heterotrimeric G proteins (G(12) and G(13)) by agonist-activated receptors remains unclear. For example, the identity of receptors that couple unequivocally to G(12) and G(13) and how signals are allocated among these and other G proteins remain open questions. Part of the problem in understandin...
Article
Full-text available
Different mitochondrial nitric-oxide synthase (mtNOS) isoforms have been described in rat and mouse tissues, such as liver, thymus, skeletal muscle, and more recently, heart and brain. The modulation of these variants by thyroid status, hypoxia, or gene deficiency opens a broad spectrum of mtNOS-dependent tissue-specific functions. In this study, a...
Article
Parkinson's disease (PD) is a worldwide neurodegenerative disorder. Although the etiology has been linked to genetic and environmental factors, curative treatment remains a challenge. Several hypotheses support different pathophysiological mechanisms related to oxidative stress, glutamate-mediated neurotoxicity, mitochondrial energetic impairment a...
Article
Oxidation of catecholamines is suggested to contribute to oxidative stress in Parkinson's disease. Nitric oxide (*NO) is able to oxidize cyclic compounds like ubiquinol; moreover, recent lines of evidence proposed a direct role of *NO and its by-product peroxynitrite in the pathophysiology of Parkinson's disease. The aim of this study was to analyz...