Dysfunction of the ER chaperone BiP accelerates the renal tubular injury

Tubular-interstitial injury plays a key role in the progression of chronic kidney disease. Although endoplasmic reticulum (ER) stress plays significant roles in the development of chronic diseases such as neurodegenerative disease, cardiomyopathy and diabetes mellitus, its pathophysiological role in chronic renal tubular cell injury remains unknown. BiP is an essential chaperone molecule that helps with proper protein folding in the ER. Recently, we have produced a knock-in mouse that expresses a mutant-BiP in which the retrieval sequence to the ER is deleted in order to elucidate physiological processes that are sensitive to ER functions in adulthood. The heterozygous mutant-BiP mice showed significant tubular-interstitial lesions with aging. Furthermore, proteinuria induced by chronic protein overload accelerated the tubular-interstitial lesions in the mutant mice, accompanying caspase-12 activation and tubular cell apoptosis. These results suggest that the ER stress pathway is significantly involved in the pathophysiology of chronic renal tubular-interstitial injury in vivo.     

ERα-negative and triple negative breast cancer: Molecular features and potential therapeutic approaches

Triple negative breast cancer (TNBC) is a type of aggressive breast cancer lacking the expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor-2 (HER-2). TNBC patients account for approximately 15% of total breast cancer patients and are more prevalent among young African, African-American and Latino women patients. The currently available ER-targeted and Her-2-based therapies are not effective for treating TNBC. Recent studies have revealed a number of novel features of TNBC. In the present work, we comprehensively addressed these features and discussed potential therapeutic approaches based on these features for TNBC, with particular focus on: 1) the pathological features of TNBC/basal-like breast cancer; 2) E₂/ERβ-mediated signaling pathways; 3) G-protein coupling receptor-30/epithelial growth factor receptor (GPCR-30/EGFR) signaling pathway; 4) interactions of ERβ with breast cancer 1/2 (BRCA1/2); 5) chemokine CXCL8 and related chemokines; 6) altered microRNA signatures and suppression of ERα expression/ERα-signaling by micro-RNAs; 7) altered expression of several pro-oncongenic and tumor suppressor proteins; and 8) genotoxic effects caused by oxidative estrogen metabolites. Gaining better insights into these molecular pathways in TNBC may lead to identification of novel biomarkers and targets for development of diagnostic and therapeutic approaches for prevention and treatment of TNBC.     

Rapid extranuclear signaling by the estrogen receptor (ER): MNAR couples ER and Src to the MAP kinase signaling pathway

In addition to their well-studied ability to transactivate the expression of many genes, estrogen receptors (ERs) also effect cytoplasmic changes occurring too quickly to be accounted for by gene expression. Indeed, these immediate, "nongenomic" effects have been intensely studied, but the identification of important protein partners in quick ER-mediated signaling has lagged behind. Now, Wong et al. have identified MNAR (modulator of nongenomic activity of estrogen receptor) as an adaptor protein that allows the ER to bridge the signaling pathways of tyrosine kinases (i.e., Src) and the mitogen-activated protein kinase (MAPK) cascade. The MNAR-ER complex also appears to positively influence ER-mediated gene expression.     

ER signaling is activated to protect human HaCaT keratinocytes from ER stress induced by environmental doses of UVB

Proteins are folded properly in the endoplasmic reticulum (ER). Various stress such as hypoxia, ischemia and starvation interfere with the ER function, causing ER stress, which is defined by the accumulation of unfolded protein (UP) in the ER. ER stress is prevented by the UP response (UPR) and ER-associated degradation (ERAD). These signaling pathways are activated by three major ER molecules, ATF6, IRE-1 and PERK. Using HaCaT cells, we investigated ER signaling in human keratinocytes irradiated by environmental doses of ultraviolet B (UVB). The expression of Ero1-Lα, an upstream signaling molecule of ER stress, decreased at 1-4 h after 10 mJ/cm² irradiation, indicating that the environmental dose of UVB-induced ER stress in HaCaT cells, without growth retardation. Furthermore, expression of intact ATF6 was decreased and it was translocated to the nuclei. The expression of XBP-1, a downstream molecule of IRE-1, which is an ER chaperone whose expression is regulated by XBP-1, and UP ubiquitination were induced by 10 mJ/cm² UVB at 4 h. PERK, which regulates apoptosis, was not phosphorylated. Our results demonstrate that UVB irradiation generates UP in HaCaT cells and that the UPR and ERAD systems are activated to protect cells from UVB-induced ER stress. This is the first report to show ER signaling in UVB-irradiated keratinocytes.     

Estrogen enhances uptake of amyloid beta-protein by microglia derived from the human cortex

In recent years, inflammatory mechanisms have been increasingly appreciated as important steps in the pathology of Alzheimer's disease (AD). There are two pathological defects in AD: chronic inflammation and impaired clearance of amyloid beta-peptide (Abeta). In the periphery, estrogen both increases macrophage phagocytosis and has antiinflammatory effects. If estrogen had a similar effect in the CNS, it could reverse inflammatory defects in AD. Although microglia are a key component of the immune system and help clear Abeta deposits in the AD brain, little is known about the effects of estrogen on CNS microglia. Therefore, we sought to determine the relationship between estrogen treatment and internalization of Abeta by microglia by quantifying the internalization of aggregated Abeta by human cortical microglia. Abeta uptake was found to be dose- and time-dependent in cultured microglia. Increased Abeta uptake was observed at 1.5 and 24 h after addition of aggregated Abeta (50, 100, or 1,000 nM: Abeta), and this uptake was enhanced by pretreatment with estrogen. The expression of estrogen receptor (ER) beta (ER-beta) was also up-regulated by estrogen treatment. Cells cotreated with ICI 182,780, an ER antagonist, showed significantly reduced internalization of Abeta in cultured microglia. These results indicate that microglia express an ER-beta but that the effect of estrogen on enhancing clearance of Abeta may be related to the receptor-independent action of estrogen or to nonclassical ER effects of estrogen. Thus, stimulation of the ER might contribute to the therapeutic action of estrogen in the treatment of AD.