Hypoxia-inducible factor-1 (HIF-1) is a major transcription factor sensitive to oxygen levels, which responds to stress factors under both hypoxic and nonhypoxic conditions. UV irradiation being a common stressor of skin, we looked at the effect of UVB on HIF-1␣ expression in keratinocytes. We found that UVB induces a biphasic HIF-1␣ variation through reactive oxygen species (ROS) generation. Whereas rapid production of cytoplasmic ROS down-regulates HIF-1␣ expression, delayed mitochondrial ROS generation results in its up-regulation. Indeed, activation of p38 MAPK and JNK1 mediated by mitochondrial ROS were required for HIF-1␣ phosphorylation and accumulation after UVB irradiation. Our experiments also revealed a key role of HIF-1␣ in mediating UVB-induced apoptosis. We conclude that the broad impact of the HIF-1 transcription factor on gene expression could make it a key regulator of UV-responsive genes and photocarcinogenesis. Solar UV radiation is the major risk factor for the development of skin cancer, the most common malignancy in the world. Several factors participate in the human natural photoprotective barrier, including constitutive and UV-induced pigmentation, stratum corneum thickness, UV-induced immune responses, UV-induced apoptosis, antioxidant defense, and DNA repair systems (1, 2). To develop a strategy for the prevention and the therapy of skin cancer, relationships between the various cellular signaling pathways that modulate cellular responses to UV irradiation in skin cells require a more indepth understanding. Within this complex group of UV-induced cellular responses, the role of ROS 3 appears central with dual effects (3). On one hand, an increase in ROS concentrations following UVB irradiation leads to cytotoxicity through protein, lipid, and DNA oxidation both in vitro and in vivo (4 -7). Reduction of the deleterious effects of UV-induced ROS by reinforcement of the antioxidant defense supports this notion (8 -10). On the other hand, ROS can also act as second messenger molecules mediating the response of cells to UVB (11)(12)(13)(14). We have recently demonstrated that UVB induces ROS production in two distinct waves. Whereas the second peak in ROS concentration has a direct effect on apoptosis, the first peak could mediate signal transduction (10). In this study, we addressed the possible role of ROS as second messengers after UVB irradiation and their potential relationship with a stress-inducible transcription factor, HIF-1. This factor, so named for its exquisite sensitivity to oxygen levels in the cell environment, participates in the regulation of numerous genes involved in angiogenesis, glycolysis, apoptosis, migration, and metastasis (15-18). We decided to look at HIF-1␣ expression within the context of ROS production in keratinocytes, in response to UVB irradiation, because ROS were already known to influence HIF-1␣ regulation and hypoxia-induced apoptosis (19). Moreover, involvement of HIF in the modulation of cell responses to growth factors under normoxia in a ROS-dependen...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.