المؤلفون: Bong Woo Kim, Kwang Je Kim, Eui Ju Choi, Kyoung Wan Yoon, Hyung Chul Kim, Ssang-Goo Cho, Jun Ho Cho, Florian Lang, Myung Jin Kim, Jeehyun Kim, Hee Jae Yun, Eunkyung Kim, Sang Sun Kang, Ji Soo Chae, Sang Gil Hwang

المصدر: The EMBO Journal. 26:3075-3085

مصطلحات موضوعية: Paclitaxel, MAP Kinase Kinase 4, Down-Regulation, Apoptosis, Breast Neoplasms, Protein Serine-Threonine Kinases, Biology, medicine.disease_cause, Dexamethasone, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Immediate-Early Proteins, Serine, Downregulation and upregulation, RNA interference, medicine, Animals, Humans, Phosphorylation, Protein kinase A, Protein Kinase Inhibitors, Molecular Biology, General Immunology and Microbiology, urogenital system, General Neuroscience, JNK Mitogen-Activated Protein Kinases, Hydrogen Peroxide, Rats, Cell biology, Enzyme Activation, SGK1, RNA Interference, Oxidative stress, Protein Binding, Signal Transduction

الوصف: Serum- and glucocorticoid-inducible protein kinase 1 (SGK1) has been implicated in diverse cellular activities including the promotion of cell survival. The molecular mechanism of the role of SGK1 in protection against cellular stress has remained unclear, however. We have now shown that SGK1 inhibits the activation of SEK1 and thereby negatively regulates the JNK signaling pathway. SGK1 was found to physically associate with SEK1 in intact cells. Furthermore, activated SGK1 mediated the phosphorylation of SEK1 on serine 78, resulting in inhibition of the binding of SEK1 to JNK1, as well as to MEKK1. Replacement of serine 78 of SEK1 with alanine abolished SGK1-mediated SEK1 inhibition. Oxidative stress upregulated SGK1 expression, and depletion of SGK1 by RNA interference potentiated the activation of SEK1 induced by oxidative stress in Rat2 fibroblasts. Moreover, such SGK1 depletion prevented the dexamethasone-induced increase in SGK1 expression, as well as the inhibitory effects of dexamethasone on paclitaxel-induced SEK1-JNK signaling and apoptosis in MDA-MB-231 breast cancer cells. Together, our results suggest that SGK1 negatively regulates stress-activated signaling through inhibition of SEK1 function.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::102beeb7f2d8b5abcb0eecb2f9b65695Test
https://doi.org/10.1038/sj.emboj.7601755Test

المؤلفون: Jung-Hyun Kim, Ssang-Goo Cho, Yong-Jin Kang, Eung-Ryoung Lee

المصدر: Biological and Pharmaceutical Bulletin. 30:32-37

مصطلحات موضوعية: Keratinocytes, Cell type, Programmed cell death, Time Factors, Cell Survival, Ultraviolet Rays, Pharmaceutical Science, Apoptosis, Biology, Antioxidants, Cell Line, Structure-Activity Relationship, chemistry.chemical_compound, Humans, Cell Proliferation, Flavonoids, Pharmacology, chemistry.chemical_classification, Reactive oxygen species, Molecular Structure, Caspase 3, Cell growth, Dose-Response Relationship, Radiation, General Medicine, Eriodictyol, Enzyme Activation, HaCaT, chemistry, Biochemistry, Cell culture, Flavanones, Poly(ADP-ribose) Polymerases, Reactive Oxygen Species, Sunscreening Agents

الوصف: Recently, considerable scientific and therapeutic interest has focused on the structure and functions of the flavonoids. In a previous study, we suggested that hydroxyl (OH) substitutions on specific carbons in the skeleton of the flavonoids might significantly affect their apoptosis-modulating properties. Here, to investigate the effect of various OH substitutions on their diphenylpropane (C6C3C6) skeleton carbons, we selected 10 different flavonoids and assessed their role on UV-induced apoptosis of human keratinocytes, the principal cell type of epidermis. The results showed that 5,7,3',4'-tetrahydroxylflavanone (eriodictyol) and 3,4'-dihydroxy flavone (3,4'-DHF) had a positive effect on cell proliferation of human HaCaT keratinocytes. Treatment with eriodictyol in particular resulted in significant suppression of cell death induced by ultraviolet (UV) light, a major skin-damaging agent. We found that eriodictyol treatment apparently reduced the percentage of apoptotic cells and the cleavage of poly(ADP-ribose) polymerase, concomitant with the repression of caspase-3 activation and reactive oxygen species (ROS) generation. The anti-apoptotic and anti-oxidant effects of eriodictyol were also confirmed in UV-induced cell death of normal human epidermal keratinocyte (NHEK) cells. Taken together, these findings suggest that eriodictyol can be used to protect keratinocytes from UV-induced damage, implying the presence of a complex structure-activity relationship (SAR) in the differential apoptosis-modulating activities of various flavonoids.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a1affab94f1fcc67eb3e917776e1e68eTest
https://doi.org/10.1248/bpb.30.32Test

المؤلفون: Shoichi Takahashi, Ze'ev Ronai, Takayuki Kadoya, Toshiki Watanabe, Hasem Habelhah, Ssang-Goo Cho

المصدر: The EMBO journal. 23(2)

مصطلحات موضوعية: TRAF2, p38 mitogen-activated protein kinases, Ubiquitin-Protein Ligases, Chromosomal translocation, IκB kinase, Ubiquitin-conjugating enzyme, Biology, Models, Biological, p38 Mitogen-Activated Protein Kinases, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, chemistry.chemical_compound, Mice, Membrane Microdomains, hemic and lymphatic diseases, Animals, Humans, Reed-Sternberg Cells, Molecular Biology, Ubiquitins, Cytoskeleton, Zinc finger, Cyclodextrins, General Immunology and Microbiology, Tumor Necrosis Factor-alpha, General Neuroscience, Cell Membrane, beta-Cyclodextrins, JNK Mitogen-Activated Protein Kinases, NF-kappa B, Proteins, NF-κB, NFKB1, TNF Receptor-Associated Factor 2, Cell biology, Protein Structure, Tertiary, Enzyme Activation, Protein Transport, chemistry, Ubiquitin-Conjugating Enzymes, I-kappa B Proteins, RNA Interference, Mitogen-Activated Protein Kinases

الوصف: TRAF2 is a RING finger protein that regulates the cellular response to stress and cytokines by controlling JNK, p38 and NF-kappaB signaling cascades. Here, we demonstrate that TRAF2 ubiquitination is required for TNFalpha-induced activation of JNK but not of p38 or NF-kappaB. Intact RING and zinc finger domains are required for TNFalpha-induced TRAF2 ubiquitination, which is also dependent on Ubc13. TRAF2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of JNK. Inhibition of Ubc13 expression by RNAi resulted in inhibition of TNFalpha-induced TRAF2 translocation and impaired activation of JNK but not of IKK or p38. TRAF2 aggregates in the cytoplasm, as seen in Hodgkin-Reed-Sternberg lymphoma cells, resulting in constitutive NF-kappaB activity but failure to activate JNK. These findings demonstrate that the TRAF2 RING is required for Ubc13-dependent ubiquitination, resulting in translocation of TRAF2 to an insoluble fraction and activation of JNK, but not of p38 or NF-kappaB. Altogether, our findings highlight a novel mechanism of TRAF2-dependent activation of diverse signaling cascades that is impaired in Hodgkin-Reed-Sternberg cells.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f00481e5345d13f6780201e84288a9f7Test
https://pubmed.ncbi.nlm.nih.gov/14713952Test

المؤلفون: Myung Jin Kim, Jin Woo Kim, Jieun Lee, Ssang-Goo Cho, Eun Gyung Cho, Eui Ju Choi

المصدر: The Journal of biological chemistry. 278(16)

مصطلحات موضوعية: Time Factors, Apoptosis, Mitogen-activated protein kinase kinase, Biochemistry, MAP2K7, Glycogen Synthase Kinase 3, Mice, Phosphatidylinositol 3-Kinases, ASK1, Enzyme Inhibitors, Cells, Cultured, Glutathione Transferase, Phosphoinositide-3 Kinase Inhibitors, Mice, Knockout, biology, Chemistry, Cell biology, Mitogen-Activated Protein Kinases, Wortmannin, Protein Binding, Signal Transduction, animal structures, Ultraviolet Rays, MAP Kinase Kinase Kinase 1, macromolecular substances, Protein Serine-Threonine Kinases, Transfection, Cell Line, Axin Protein, Proto-Oncogene Proteins, Animals, Humans, Mitogen-Activated Protein Kinase 8, Molecular Biology, Glycogen Synthase Kinase 3 beta, MAP kinase kinase kinase, Cyclin-dependent kinase 4, Akt/PKB signaling pathway, Tumor Necrosis Factor-alpha, Cyclin-dependent kinase 2, Proteins, Cell Biology, Fibroblasts, Molecular biology, Precipitin Tests, Androstadienes, Enzyme Activation, Repressor Proteins, biology.protein, Cyclin-dependent kinase 9, Lithium Chloride, Proto-Oncogene Proteins c-akt

الوصف: Glycogen synthase kinase 3beta (GSK3 beta) is implicated in many biological events, including embryonic development, cell differentiation, apoptosis, and insulin response. GSK3 beta has now been shown to induce activation of the mitogen-activated protein kinase kinase kinase MEKK1 and thereby to promote signaling by the stress-activated protein kinase pathway. GSK3 beta-binding protein blocked the activation of MEKK1 by GSK3 beta in human embryonic kidney 293 (HEK293) cells. Furthermore, co-immunoprecipitation analysis revealed a physical association between endogenous GSK3 beta and MEKK1 in HEK293 cells. Overexpression of axin1, a GSK3 beta-regulated scaffolding protein, did not affect the physical interaction between GSK3 beta and MEKK1 in transfected HEK293 cells. Exposure of cells to insulin inhibited the activation of MEKK1 by GSK3 beta, and this inhibitory effect of insulin was abolished by the phosphatidylinositol 3-kinase inhibitor wortmannin. Furthermore, MEKK1 activity under either basal or UV- or tumor necrosis factor alpha-stimulated conditions was reduced in embryonic fibroblasts derived from GSK3 beta knockout mice compared with that in such cells from wild-type mice. Ectopic expression of GSK3 beta increased both basal and tumor necrosis factor alpha-stimulated activities of MEKK1 in GSK3 beta(-/-) cells. Together, these observations suggest that GSK3 beta functions as a natural activator of MEKK1.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9c54c1a89057960326fd99b31e094e64Test
https://pubmed.ncbi.nlm.nih.gov/12584189Test