Estrogen and Cancer.
ABSTRACT Estrogen exhibits a broad spectrum of physiological functions ranging from regulation of the menstrual cycle and reproduction to modulation of bone density, brain function, and cholesterol mobilization. Despite the beneficial actions of endogenous estrogen, sustained exposure to exogenous estrogen is a well-established risk factor for various cancers. We summarize our current understanding of the molecular mechanisms of estrogen signaling in normal and cancer cells and discuss the major challenges to the existing antiestrogen therapy. Expected final online publication date for the Annual Review of Physiology Volume 75 is February 10, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
- SourceAvailable from: Takashi Koyama[Show abstract] [Hide abstract]
ABSTRACT: The role of juvenile hormone (JH) in regulating the timing and nature of insect molts is well-established. Increasing evidence suggests that JH is also involved in regulating final insect size. Here we elucidate the developmental mechanism through which JH regulates body size in developing Drosophila larvae by genetically ablating the JH-producing organ, the corpora allata (CA). We found that larvae that lack CA pupariated at smaller sizes than control larvae due to a reduced larval growth rate. Neither the timing of the metamorphic molt nor the duration of larval growth was affected by the loss of JH. Further, we show that the effects of JH on growth rate are dependent on the forkhead box O transcription factor (FOXO), which is negatively regulated by the insulin-signaling pathway. Larvae that lacked the CA had elevated levels of FOXO activity, whereas a loss-of-function mutation of FOXO rescued the effects of CA ablation on final body size. Finally, the effect of JH on growth appears to be mediated, at least in part, via ecdysone synthesis in the prothoracic gland. These results indicate a role of JH in regulating growth rate via the ecdysone- and insulin-signaling pathways.Proceedings of the National Academy of Sciences 04/2014; · 9.81 Impact Factor
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ABSTRACT: Increasing evidence demonstrates a connection between growth factor function (including brain-derived neurotrophic factor, BDNF), glucocorticoid levels (one of the steroid hormones), and the pathophysiology of depressive disorders. Because both BDNF and glucocorticoids regulate synaptic function in the central nervous system, their functional interaction is of major concern. Interestingly, alterations in levels of estrogen, another steroid hormone, may play a role in depressive-like behavior in postpartum females with fluctuations of BDNF-related molecules in the brain. BDNF and cytokines, which are protein regulators of inflammation, stimulate multiple intracellular signaling cascades involved in neuropsychiatric illness. Pro-inflammatory cytokines may increase vulnerability to depressive symptoms, such as the increased risk observed in patients with cancer and/or autoimmune diseases. In this review, we discuss the possible relationship between inflammation and depression, in addition to the cross-talk among cytokines, BDNF, and steroids. Further, since nutritional status has been shown to affect critical pathways involved in depression through both BDNF function and the monoamine system, we also review current evidence surrounding diet and supplementation (e.g., flavonoids) on BDNF-mediated brain functions.Frontiers in Psychiatry 01/2014; 5:136.
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ABSTRACT: The steroid hormone receptors regulate important physiological functions such as reproduction, metabolism, immunity, and electrolyte balance. Mutations within steroid receptors result in endocrine disorders and can often drive cancer formation and progression. Despite the conserved three-dimensional structure shared among members of the steroid receptor family and their overlapping DNA binding preference, activation of individual steroid receptors drive unique effects on gene expression. Here, we present the first structure of the human mineralocorticoid receptor DNA binding domain, in complex with a canonical DNA response element. The overall structure is similar to the glucocorticoid receptor DNA binding domain, but small changes in the mode of DNA binding and lever arm conformation may begin to explain the differential effects on gene regulation by the mineralocorticoid and glucocorticoid receptors. In addition, we explore the structural effects of mineralocorticoid receptor DNA binding domain mutations found in type I pseudohypoaldosteronism and multiple types of cancer.PLoS ONE 01/2014; 9(9):e107000. · 3.53 Impact Factor