RESUMEN
The nicotinamide adenine dinucleotide phosphate oxidase (NOX) family enzymes are involved in several physiological functions. However, their roles in keratinocyte responses to UV radiation have not been clearly elucidated. This study shows that, among other NOX family members, UVB irradiation results in a biphasic activation of NOX1 that plays a critical role in defining keratinocyte fate through the modulation of the DNA damage response network. Indeed, suppression of both bursts of UVB-induced NOX1 activation by using a specific peptide inhibitor of NOX1 (InhNOX1) is associated with increased nucleotide excision repair efficiency and reduction of apoptosis, which is finally translated into decreased photocarcinogenesis. On the contrary, when only the second peak of UVB-induced NOX1 activation is blocked, both nucleotide excision repair efficiency and apoptosis are decreased. Our results show that inhibition of NOX1 activation could be a promising target for the prevention and treatment of UVB-induced skin cancer in nucleotide excision repair-proficient and -deficient patients.
Asunto(s)
Carcinogénesis/efectos de la radiación , Queratinocitos/efectos de la radiación , NADH NADPH Oxidorreductasas/genética , NADH NADPH Oxidorreductasas/efectos de la radiación , NADPH Oxidasas/efectos de los fármacos , Rayos Ultravioleta/efectos adversos , Animales , Apoptosis/genética , Apoptosis/efectos de la radiación , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Queratinocitos/citología , Ratones , Ratones Pelados , Ratones Transgénicos , Terapia Molecular Dirigida , NADPH Oxidasa 1 , NADPH Oxidasas/metabolismo , Neoplasias Inducidas por Radiación/fisiopatología , Neoplasias Inducidas por Radiación/prevención & control , Pirazoles/farmacología , Pirazolonas , Piridinas/farmacología , Piridonas , Distribución Aleatoria , Factores de Riesgo , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/fisiopatologíaRESUMEN
Xeroderma pigmentosum type C (XP-C) is characterized mostly by a predisposition to skin cancers and accelerated photoaging, but little is known about premature skin aging in this disease. By comparing young and old mice, we found that the level of progerin and p16(INK4a) expression, ß-galactosidase activity, and reactive oxygen species, which increase with age, were higher in young Xpc(-/-) mice than in young Xpc(+/+) ones. The expression level of mitochondrial complexes and mitochondrial functions in the skin of young Xpc(-/-) was as low as in control aged Xpc(+/+)animals. Furthermore, the metabolic profile in young Xpc(-/-) mice resembled that found in aged Xpc(+/+) mice. Furthermore, premature skin aging features in young Xpc(-/-) mice were mostly rescued by inhibition of nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) activity by using a NOX1 peptide inhibitor, suggesting that the continuous oxidative stress due to overactivation of NOX1 has a causative role in the underlying pathophysiology.
Asunto(s)
Proteínas de Unión al ADN/genética , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/metabolismo , Proteínas Nucleares/metabolismo , Precursores de Proteínas/metabolismo , Envejecimiento de la Piel , Proteínas Adaptadoras Transductoras de Señales , Animales , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Humanos , Queratinocitos/citología , Lamina Tipo A , Luz , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , NADPH Oxidasa 1 , Estrés Oxidativo , Proteínas/genética , Especies Reactivas de Oxígeno/metabolismo , Xerodermia Pigmentosa/metabolismo , beta-Galactosidasa/metabolismoRESUMEN
Besides lung, postnatal human epidermis is the only epithelium in direct contact with atmospheric oxygen. Skin epidermal oxygenation occurs mostly through atmospheric oxygen rather than tissue vasculature, resulting in a mildly hypoxic microenvironment that favors increased expression of hypoxia-inducible factor-1α (HIF-1α). Considering the wide spectrum of biological processes, such as angiogenesis, inflammation, bioenergetics, proliferation, motility, and apoptosis, that are regulated by this transcription factor, its high expression level in the epidermis might be important to HIF-1α in skin physiology and pathophysiology. Here, we review the role of HIF-1α in cutaneous angiogenesis, skin tumorigenesis, and several skin disorders.
Asunto(s)
Carcinoma de Células Escamosas/fisiopatología , Epidermis/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Neovascularización Fisiológica/fisiología , Neoplasias Cutáneas/fisiopatología , Carcinoma de Células Escamosas/metabolismo , Humanos , Oxígeno/metabolismo , Enfermedades de la Piel/metabolismo , Enfermedades de la Piel/fisiopatología , Neoplasias Cutáneas/metabolismoRESUMEN
Tissue stem cells must be endowed with superior maintenance and repair systems to ensure genomic stability over multiple generations, which would be less necessary in more differentiated cells. We previously reported that human keratinocyte stem cells were more resistant to ionizing radiation toxicity than their direct progeny, the keratinocyte progenitor cells. In the present study we addressed the mechanisms underlying this difference. Investigations of DNA repair showed that both single and double DNA strand breaks were repaired more rapidly and more efficiently in stem cells than in progenitors. As cell signaling is a key regulatory step in the management of DNA damage, a gene profiling study was performed. Data revealed that several genes of the fibroblast growth factor type 2 (FGF2) signaling pathway were induced by DNA damage in stem cells and not in progenitors. Furthermore, an increased content of the FGF2 protein was found in irradiated stem cells, both for the secreted and the cellular forms of the protein. To examine the role of endogenous FGF2 in DNA repair, stem cells were exposed to FGF2 pathway inhibitors. Blocking the FGF2 receptor (FGF receptor 1) or the kinase (Ras-mitogen-activated protein kinase 1) resulted in a inhibition of single and double DNA strand-break repair in the keratinocyte stem cells. Moreover, supplementing the progenitor cells with exogenous FGF2 activated their DNA repair. We propose that, apart from its well-known role as a strong mitogen and prosurvival factor, FGF2 helps to maintain genomic integrity in stem cells by activating stress-induced DNA repair.
Asunto(s)
Roturas del ADN de Doble Cadena , Roturas del ADN de Cadena Simple , Reparación del ADN , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Queratinocitos/metabolismo , Transducción de Señal , Células Madre/metabolismo , Anticuerpos Monoclonales/farmacología , Butadienos/farmacología , Ciclo Celular , Células Cultivadas , Ensamble y Desensamble de Cromatina , Ensayo Cometa , Factor 2 de Crecimiento de Fibroblastos/antagonistas & inhibidores , Factor 2 de Crecimiento de Fibroblastos/genética , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Inestabilidad Genómica , Histonas/metabolismo , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/efectos de la radiación , Nitrilos/farmacología , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Recombinantes/metabolismo , Serina , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/efectos de la radiación , Células Madre/efectos de los fármacos , Células Madre/efectos de la radiación , Factores de TiempoRESUMEN
Stem cells have been described in most adult tissues, where they play a key role in maintaining tissue homeostasis. As they self-renew throughout life, accumulating genetic anomalies can compromise their genomic integrity and potentially give rise to cancer. Stem cells (SCs) may thus be a major target of radiation carcinogenesis. In addition, unrepaired genotoxic damage may cause cell death and stem cell pool depletion, impairing lineage functionality and accelerating aging. Developments in SC biology enabled the characterization of the responses of stem cells to genotoxic stress and their role in tissue damage. We here examine how these cells react to ionizing radiation (IR), and more specifically their radiosensitivity, stress signaling and DNA repair. We first review embryonic SCs, as a paradigm of primitive pluripotent cells, then three adult tissues, bone marrow, skin and intestine, capable of long-term regeneration and at high risk for acute radiation syndromes and long-term carcinogenesis. We discuss IR disruption of the fine balance between maintenance of tissue homeostasis and genomic stability. We show that stem cell radiosensitivity does not follow a unique model, but differs notably according to the turnover rates of the tissues.