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The endoplasmic reticulum (ER) plays an important role in the regulation of protein synthesis. Alterations in the folding capacity of the ER induce stress, which activates three ER sensors that mediate the unfolded protein response (UPR). Components of the pathways regulated by these sensors have been shown to regulate autophagy. The last corresponds to a mechanism of self‐eating and recycling important for proper cell maintenance. Ultraviolet radiation (UV) is an external damaging stimulus that is known for inducing oxidative stress, and DNA, lipid and protein damage. Many controversies exist regarding the role of UV‐inducing ER stress or autophagy. However, a connection between the three of them has not been addressed. In this review, we will discuss the contradictory theories regarding the relationships between UV radiation with the induction of ER stress and autophagy, as well as hypothetic connections between UV, ER stress and autophagy. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) plays an important role in the regulation of protein synthesis. Alterations in the folding capacity of the ER induce stress, which activates three ER sensors that mediate the unfolded protein response (UPR). Components of the pathways regulated by these sensors have been shown to regulate autophagy. The last corresponds to a mechanism of self‐eating and recycling important for proper cell maintenance. Ultraviolet radiation (UV) is an external damaging stimulus that is known for inducing oxidative stress, and DNA, lipid and protein damage. Many controversies exist regarding the role of UV‐inducing ER stress or autophagy. However, a connection between the three of them has not been addressed. In this review, we will discuss the contradictory theories regarding the relationships between UV radiation with the induction of ER stress and autophagy, as well as hypothetic connections between UV, ER stress and autophagy. [ABSTRACT FROM AUTHOR]

Ultraviolet B‐light (UVB) has been often used as a "physiological" UV in photobiology studies. How representative and equivalent these studies are compared to the effect of the sunlight is always of great interest. We now characterized the spectrum and intensity of two commonly used UV sources, a UVB lamp and a UVA‐340 lamp which simulate the solar spectrum in the UVB/UVA range in the presence or absence of a UVB band pass filter that reduces >80% UVA from the UVA‐340 lamp. The spectrum of each lamp was used in computational modeling for skin penetration. The effects of the lamps on endoplasmic reticulum (ER)‐stress response and DNA damage in cultured keratinocytes HaCaT cells were analyzed. Our data show that the UVB lamp is a better inducer for both eIF2α phosphorylation and PERK modification, as well as a better reducer of ATF6 expression. The UVB lamp is also the best inducer of gamma‐H2AX expression and cyclobutane pyrimidine dimers formation. However, the UVA‐340 lamp is a better inducer for ATF4 expression. Our results indicate that different spectral characteristics of UV lamps can produce different results for the activation of the ER‐stress responses and the differences do not always follow a defined pattern. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO·) plays an important role in the regulation of redox balance in keratinocytes post‐UVB exposure. Since endothelial cells releases NO· for a prolonged time post‐UVB, we determined whether human umbilical vein endothelial cells (HUVEC) could have an effect on UVB‐induced DNA damage and transformation of their adjacent keratinocytes (HaCaT) using a 3D cell co‐culturing system. Our data show that the levels of DNA breaks and/or cyclobutane pyrimidine dimer (CPD) along with γH2AX are higher in the co‐cultured than in the mono‐cultured keratinocytes post‐UVB. The NO· level in the co‐cultured cells is increased approximately 3‐fold more than in mono‐cultured HaCaT cells within 1‐hour post‐UVB but then is reduced quickly in co‐cultured HaCaT cells comparing to mono‐cultured cells from 6 to 24 h post‐UVB. However, the peroxynitrite (ONOO−) level is higher in the co‐cultured than in the mono‐cultured HaCaT cells in whole period post‐UVB. Furthermore, while expression level of inducible nitric oxide synthase (iNOS) is increased, the ratio of coupled/uncoupled eNOS is reduced in co‐cultured HaCaT cells compared to mono‐cultured HaCaT cells. Finally, the co‐cultured cells have a significantly increased transformation efficiency after repeating UVB exposure compared to mono‐culture HaCaT cells. Our results suggest that endothelial cells could enhance NO·/ONOO− imbalance and promote transformation of adjacent keratinocytes. Upon UVB exposure, the uncoupled eNOS produces superoxide O2·− instead of NO·. Then O2·− reacts rapidly with NO·, which could be produced by iNOS, to form ONOO− resulting in an increase of CPD formation and cell transformation. [ABSTRACT FROM AUTHOR]

Cold‐inducible RNA binding protein (CIRP) is a stress‐inducible protein, which could be activated by various cellular stresses, such as hypothermia, hypoxia and UV irradiation. Our previous study indicated that UVB radiation (3 mJ cm−2) induces CIRP expression, which promotes keratinocytes growth, survival and eventually transformation via activation of STAT3‐Bag‐1/S signaling cascade. However, the mechanism(s) of CIRP in regulating p‐STAT3 activation and Bag‐1/S expression have not been fully elucidated. In this study, we demonstrate that repeated exposure of UVB radiation (3 mJ cm−2) or overexpression of CIRP could lead to an elevation of the phosphorylation of Janus kinase (JAK) family proteins (JAK2 and JAK3) in HaCaT cells. The increased phosphorylation of the JAKs correlates to an increased phosphorylation of STAT3 (p‐STAT3) in the cells; inhibiting JAKs using JAK inhibitor I lead to a reduction of STAT3 phosphorylation and Bag‐1/S expression in wild type HaCaT and CIRP stably transfected HaCaT cells with or without UVB exposure. Furthermore, our data indicated that inhibiting the downstream factor of CIRP, NF‐κB, using BAY 11‐7085 could also decrease the p‐STAT3. These results lead us to propose that CIRP mediates the activation of STAT3‐Bag‐1/S signaling cascade via activating the JAKs and NF‐κB signaling pathways. Cold‐inducible RNA binding protein (CIRP) is a stress‐inducible protein, which could be activated by UV irradiation. In this study, we demonstrate that repeated exposure of UVB (3 mJ cm−2) or overexpression of CIRP could lead to an elevation of the phosphorylation of Janus kinase (JAK) family proteins in HaCaT cells. The increased phosphorylation of the JAKs correlates to an increased phosphorylation of STAT3 (p‐STAT3) in the cells. In addition, inhibiting NF‐κB could also decrease p‐STAT3. These results lead us to propose that CIRP mediates the activation of STAT3‐Bag‐1/S signaling cascade via activating the JAKs and NF‐κB signaling pathways. [ABSTRACT FROM AUTHOR]

Human homolog double minute 2 (hdm2), an oncoprotein, which binds to tumor suppressor p53 to facilitate its degradation, has been known to contribute to tumorigenesis. Its splicing variants are reported to be highly expressed in many cancers and can be induced by ultraviolet B light ( UVB). However, the mechanisms of how UVB radiation induces hdm2 alternative splicing still remain unclear. In this study, we investigated the roles of two common splicing factors, heterogeneous nuclear ribonucleoproteins (hn RNP) A1 and serine/arginine-rich splicing factor 1 ( SRSF1), in regulating UVB-induced hdm2 splicing. Our study indicated that while the expression of both hn RNP A1 and SRSF1 are induced, only hn RNP A1 is involved in hdm2 alternative splicing upon UVB irradiation. Overexpression of hn RNP A1 resulted in decrease of full-length hdm2 (hdm2- FL) and increase of hdm2B, one of hdm2 alternate-splicing forms; while down-regulated hn RNP A1 expression led to the decrease of the hdm2- FL and hdm2B in HaCaT cells. Protein- mRNA binding assay confirmed that UVB irradiation could increase the binding of hn RNP A1 to hdm2 pre- mRNA. In conclusion, we elucidated that UVB induces alternative splicing of hdm2 by increasing the expression and the binding of hn RNP A1 to hdm2 full-length mRNA. [ABSTRACT FROM AUTHOR]

Alternative splicing plays an important role in proteasome diversity and gene expression regulation in eukaryotic cells. Hdm2, the human homolog of mdm2 (murine double minute oncogene 2), is known to be an oncogene as its role in suppression of p53. Hdm2 alternative splicing, occurs in both tumor and normal tissues, is believed to be a response of cells for cellular stress, and thus modulate p53 activity. Therefore, understanding the regulation of hdm2 splicing is critical in elucidating the mechanisms of tumor development and progression. In this study, we determined the effect of ultraviolet B light (UVB) on alternative splicing of hdm2. Our data indicated that UVB (50 mJ cm-2) alone is not a good inducer of alternative splicing of hdm2. The less effectiveness could be due to the induction of ROS and p53 by UVB because removing ROS by L-NAC (10 mM) in p53 null cells could lead to alternative splicing of hdm2 upon UVB irradiation. [ABSTRACT FROM AUTHOR]

Nuclear Factor Kappa-B ( NF-κB) is a transcription factor that controls expression of genes involved in the immune and inflammatory responses as well as being a key component in the onset of cancers. In this study, we provided evidence that mitogen- and stress-activated protein kinase ( MSK1) is responsible for a noncanonical late-phase activation of NF-κB upon UVB irradiation. Our data demonstrated that following UVB irradiation, MSK1 is activated via phosphorylation at the 24 h time point coinciding with translocation of NF-κB into the nucleus. Investigations into the signaling pathways upstream of MSK1 through the use of specific inhibitors for mitogen-activated protein kinase and p38 revealed that both kinases are required for full phosphorylation during the late phase (24 h), while p38 is paramount for phosphorylation during the early phase (6 h). Electromobility shift assays ( EMSA) showed that inhibition of MSK1 resulted in a marked reduction in NF-κB binding affinity without altering the nuclear translocation of NF-κB. Supershift EMSA implicate that the p65, but not p50, isoform of NF-κB is involved in late-phase activation in response to UVB irradiation. Together, the results of these studies shed light onto a novel pathway of MSK1-mediated late-phase activation of NF-κB in response to UVB irradiation. [ABSTRACT FROM AUTHOR]

Modification of major lipid raft components, such as cholesterol and ceramide, plays a role in regulation of programmed cell death under various stimuli. However, the relationship between cholesterol level modification and the activation of apoptotic signaling cascades upon UVB light has not been established. In this report, we demonstrate that upon UVB irradiation cholesterol levels in membrane rafts of skin cells increase, which leads to Fas-receptor (Fas) aggregation in the rafts. Utilizing a continuous velocity floatation technique, we show that Fas accumulated in the lipid rafts of human melanoma M624 cells after UVB irradiation. The subsequent events of death-inducing signaling complex formation were also detected in the lipid raft fractions. Depletion of cholesterol by methyl-β-cyclodextrin reduces Fas aggregation, while overloading increases. Disruption of lipid rafts also prevents Fas death domain-associated protein (Daxx) from dissociating from Fas in the lipid rafts, which is accompanied with a reduced apoptotic, but increased nonapoptotic death of UVB-irradiated human keratinocytes, HaCaT cells. Results indicate that cholesterol located in the plasma membrane of skin cells is required for lipid raft domain formation and activation of UVB-induced apoptosis. [ABSTRACT FROM AUTHOR]

Nuclear factor-kappa B (NF-κB) plays an important role in UV-induced skin tumorigenesis. Activation of NF-κB by UV-irradiation is composed of two phases. The early phase culminates with maximal levels of DNA binding ability at 4 h postirradiation and is dependent on translational inhibition. The late-phase activation of NF-κB occurs between 16 and 48 h post-irradiation and the mechanism is not clear due to the fact that NF-κB was activated in the presence of high level of IκBα. In this report, we provide evidence that without translational inhibition, the transcription of IκBα was induced by UV-irradiation. In the late-phase of UV-induced NF-κB activation, the IκBα depletion is the combined result of regulation at both transcriptional and translational levels. Neither ubiquitination nor proteasomal degradation have detectable attributions to IκBα breakdown. We also demonstrate that UV only induced phosphorylation of p65(S276), while tumor necrosis factor-α induced phosphorylation at both Ser276 and 536 sites of p65. Based upon our results, we propose a novel mechanism for translation-regulated IκBα depletion and MSK-mediated NF-κB activation at 24 h post-UV-irradiation. [ABSTRACT FROM AUTHOR]

Insufficient exposure to sunlight increases the risk of cardiovascular diseases. Hypertensive left ventricular (LV) hypertrophy exacerbates the risks of myocardial ischemia, ventricular arrhythmias, sudden cardiac death, and heart failure. This study aimed to determine the effects of ultraviolet (UV) irradiation on LV hypertrophy and mitochondrial morphology. Eighteen 7‐week‐old Dahl salt‐sensitive (Dahl S) rats were categorized into three groups (n = 6 each) and fed sodium chloride (NaCl) diets, as follows: UV‐irradiated [UVB+A (+), 8% NaCl], non‐UV‐irradiated [UV (−), 8% NaCl], and control [UV (−), 0.3% NaCl]. UV irradiation was administered at a low intensity of 100 mJ/cm2 for 6 days per week. Echocardiography and mitochondrial analyses were performed to evaluate LV hypertrophy and cardiomyocytes, and skin tissues were stained with hematoxylin and eosin to assess the pathological abnormalities at 12 weeks of age. LV mass was significantly reduced in the UVB+A (+) and control groups compared to that in the UV (−) group. Mitochondrial structural abnormalities in cardiomyocytes were observed only in the UV (−) group, but not in the UVB+A (+) or control group. Pathological skin abnormalities were not observed in any of the three groups. These findings suggest the potential benefits of UV irradiation in hypertensive models. [ABSTRACT FROM AUTHOR]