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1.
Proc Natl Acad Sci U S A ; 115(22): E5243-E5249, 2018 05 29.
Article in English | MEDLINE | ID: mdl-29760065

ABSTRACT

NF-κB signaling plays a pivotal role in control of the inflammatory response. We investigated how the dynamics and function of NF-κB were affected by temperature within the mammalian physiological range (34 °C to 40 °C). An increase in temperature led to an increase in NF-κB nuclear/cytoplasmic oscillation frequency following Tumor Necrosis Factor alpha (TNFα) stimulation. Mathematical modeling suggested that this temperature sensitivity might be due to an A20-dependent mechanism, and A20 silencing removed the sensitivity to increased temperature. The timing of the early response of a key set of NF-κB target genes showed strong temperature dependence. The cytokine-induced expression of many (but not all) later genes was insensitive to temperature change (suggesting that they might be functionally temperature-compensated). Moreover, a set of temperature- and TNFα-regulated genes were implicated in NF-κB cross-talk with key cell-fate-controlling pathways. In conclusion, NF-κB dynamics and target gene expression are modulated by temperature and can accurately transmit multidimensional information to control inflammation.


Subject(s)
Gene Expression Regulation/physiology , NF-kappa B/metabolism , Tumor Necrosis Factor alpha-Induced Protein 3/metabolism , Tumor Necrosis Factor-alpha/metabolism , Animals , Cell Line, Tumor , Cells, Cultured , Cytokines/metabolism , Gene Expression Regulation/genetics , Gene Knockdown Techniques , Humans , Inflammation , Mice , NF-kappa B/genetics , Signal Transduction/genetics , Signal Transduction/physiology , Temperature , Tumor Necrosis Factor alpha-Induced Protein 3/analysis , Tumor Necrosis Factor alpha-Induced Protein 3/genetics
2.
Endocrinology ; 149(2): 687-94, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18006630

ABSTRACT

Estrogens have been implicated in the regulation of prolactin gene expression in man, although previous studies have not defined the molecular mechanism whereby estradiol activates the human prolactin gene promoter (hPrl). We found that estradiol induced a reproducible 1.8-fold activation of the hPrl gene promoter, using pituitary GH3 cells stably transfected with a 5000-bp hPrl promoter fragment linked to luciferase reporter gene. This activation was blocked by treatment with estrogen receptor (ER) antagonists 4-hydroxytamoxifen and ICI-182,780. Promoter deletion and mutagenesis experiments identified a functional estrogen response element (ERE) sequence 1189 bp upstream of the transcription start site that was responsible for estrogen-mediated promoter activation. This site differed from the consensus ERE sequence by two base pairs, one in each half-site. This ERE was identified to be functional through binding ERalpha in EMSAs. Chromatin immunoprecipitation assays confirmed ERalpha binding to this sequence in vivo in the absence of ligand, with increased recruitment when cells were cultured in the presence of estradiol. When cells were treated with both estradiol and TNFalpha, we observed synergistic activation of the hPrl promoter, which was mediated by the -1189-bp ERE. Mutagenesis of this ERE abolished the promoter-activating effect not only of estradiol but also of TNFalpha. These data suggest a novel, promoter-specific signaling interaction between estrogen and TNFalpha signaling, which is likely to be important for prolactin regulation in vivo.


Subject(s)
Estradiol/metabolism , Prolactin/genetics , Signal Transduction/physiology , Tumor Necrosis Factor-alpha/metabolism , Animals , Cell Line , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estrogen Antagonists/pharmacology , Fulvestrant , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Humans , Luciferases/genetics , Pituitary Gland, Anterior/cytology , Promoter Regions, Genetic/physiology , Rats , Rats, Inbred F344 , Receptors, Estrogen/metabolism , Signal Transduction/drug effects , Tamoxifen/analogs & derivatives , Tamoxifen/pharmacology
3.
Hum Reprod Update ; 12(3): 253-67, 2006.
Article in English | MEDLINE | ID: mdl-16338990

ABSTRACT

Ca(2+) is a ubiquitous intracellular messenger which encodes information by temporal and spatial patterns of concentration. In spermatozoa, several key functions, including acrosome reaction and motility, are regulated by cytoplasmic Ca(2+) concentration. Despite the very small size and apparent structural simplicity of spermatozoa, evidence is accumulating that they possess sophisticated mechanisms for regulation of cytoplasmic Ca(2+) concentration and generation of complex Ca(2+) signals. In this review, we consider the various components of the Ca(2+)-signalling 'toolkit' that have been characterized in somatic cells and summarize the evidence for their presence and activity in spermatozoa. In particular, data accumulated over the last few years show that spermatozoa possess one (and probably two) Ca(2+) stores as well as a range of plasma membrane pumps and channels. Selective regulation of the various components of the 'toolkit' by agonists probably allows spermatozoa to generate localized Ca(2+) signals despite their very small cytoplasmic volume, permitting the discrete and selective activation of cell functions.


Subject(s)
Calcium Channels/metabolism , Calcium Signaling , Calcium/metabolism , Spermatozoa/metabolism , Calcium/agonists , Calcium-Transporting ATPases/metabolism , Humans , Male
4.
Ir J Med Sci ; 159(5): 145-6, 1990 May.
Article in English | MEDLINE | ID: mdl-2397984

ABSTRACT

Subungal melanoma is a rare condition accounting for 1-3% of all melanomas. It has been associated with a poor prognosis, with a 10-30% 5 year survival usually attributed to the delay in diagnosis. Early biopsy of suspicious lesions followed by amputation of the digit in those proving positive is the treatment of choice.


Subject(s)
Melanoma/diagnosis , Nail Diseases/diagnosis , Aged , Aged, 80 and over , Clinical Protocols , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Nail Diseases/pathology , Nail Diseases/therapy , Prognosis
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