1.
BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation.
Bononi, A, Giorgi, C, Patergnani, S, Larson, D, Verbruggen, K, Tanji, M, Pellegrini, L, Signorato, V, Olivetto, F, Pastorino, S, et al
Nature. 2017;(7659):549-553
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Abstract
BRCA1-associated protein 1 (BAP1) is a potent tumour suppressor gene that modulates environmental carcinogenesis. All carriers of inherited heterozygous germline BAP1-inactivating mutations (BAP1+/-) developed one and often several BAP1-/- malignancies in their lifetime, mostly malignant mesothelioma, uveal melanoma, and so on. Moreover, BAP1-acquired biallelic mutations are frequent in human cancers. BAP1 tumour suppressor activity has been attributed to its nuclear localization, where it helps to maintain genome integrity. The possible activity of BAP1 in the cytoplasm is unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination, indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. Here we discover that BAP1 localizes at the endoplasmic reticulum. Here, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3), modulating calcium (Ca2+) release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1+/- carriers cause reduction both of IP3R3 levels and of Ca2+ flux, preventing BAP1+/- cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in BAP1+/- carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction in human carcinogenesis.
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Differential expression of calcium transport channels in placenta primary cells and tissues derived from preeclamptic placenta.
Yang, H, Kim, TH, An, BS, Choi, KC, Lee, HH, Kim, JM, Jeung, EB
Molecular and cellular endocrinology. 2013;(1-2):21-30
Abstract
Preeclampsia is a pregnancy-specific disease characterized by hypertension, proteinuria, and oxidative stress in the placenta. During the last trimester of gestation, calcium (Ca(2+)) transport from mother to fetus increases dramatically in response to the increased demand for Ca(2+) caused by bone mineralization in the fetus. Ca(2+) supplementation can significantly reduce the incidence and severity of preeclampsia or delay its onset. Ca(2+) transport channels (CTCs) include transient receptor potential vanilloid 6 (TRPV6), plasma membrane Ca(2+) ATPase (PMCA1), and Na(+)/Ca(2+) exchangers (NCKX3 or NCX1). We hypothesized that trans-placental Ca(2+) exchange in preeclamptic trophoblasts may be compensated for successful fetal bone mineralization. The roles of cell membrane channels (TRPV6, PMCA1, NCKX3 and NCX1) were examined in placental primary cells and in normotensive and preeclamptic placentas. The biomarker gene for preeclampsia, soluble fms-like tyrosine kinase-1 (sFLT1) or marker for oxygen-sensitive gene, hypoxia-sensitive inducible factor 1α (HIF-1α), were up-regulated in the preeclamptic placentas and hypoxic cells. The detection of sFLT1 and HIF-1α genes demonstrated that our experimental conditions were suitable to verify a preeclamptic condition. In women experiencing preterm labor, CTC expressions was found to be increased in the fetal and maternal regions of the preeclamptic placenta compared to the observed in normotensive placenta. During term labor, TRPV6 and PMCA1 were highly expressed in the fetal and maternal sections of preeclamptic placenta, while the expression of NCKX3 and NCX1 was reduced. In addition, the expression of CTCs was altered in hypoxia-stressed placental cells. Taken together, our findings demonstrated that the expression of CTCs was regulated by hypoxia stress in placenta tissues and cells, suggesting that our experimental in vitro hypoxic conditions were similar to those of preeclampsia. Furthermore, impaired Ca(2+) metabolism found in preeclamptic syncytiotrophoblasts was resulted from hypoxic stress, which may induce expression of Ca(2+) transport proteins in the placenta to maintain the balance between maternal and fetal Ca(2+) demand during pregnancy.
3.
Regulation and molecular mechanisms of calcium transport genes: do they play a role in calcium transport in the uterine endometrium?
Choi, KC, An, BS, Yang, H, Jeung, EB
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 2011;(5):499-504
Abstract
Maintenance of calcium (Ca) balance in the uterus is critically important for many physiological functions, including smooth muscle contraction during embryo implantation. Ca transport genes, i.e., transient receptor potential cation channel subfamily V members 5/6 (TRPV5/6), calbindins, plasma membrane Ca(2+)-ATPase 1 (PMCA1), and NCX1/NCKX3, may play roles in the uterus for Ca transport and reproductive function. Although these Ca transport genes may have a role in Ca metabolism, their role(s) and molecular mechanisms require further elucidation. In this review, we highlight the expression and regulation of Ca transport genes in the uterus to clarify their potential role(s). Since Ca transport genes are abundantly expressed in reproductive tissues in a distinct manner, they may be involved in specific uterine functions including fetal implantation, Ca homeostasis, and endometrial cell production.