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Item Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity(American Diabetes Association, 2013-11) Carobbio, Stefania; Hagen, Rachel M.; Lelliott, Christopher J.; Slawik, Marc; Medina-Gomez, Gema; Tan, Chong-Yew; Sicard, Audrey; Atherton, Helen J.; Barbarroja, Nuria; Bjursell, Mikael; Bohlooly-Y, Mohammad; Virtue, Sam; Tuthill, Antoinette; Lefai, Etienne; Laville, Martine; Wu, Tingting; Considine, Robert V.; Vidal, Hubert; Langin, Dominique; Oresic, Matej; Tinahones, Francisco J.; Manuel Fernandez-Real, Jose; Griffin, Julian L.; Sethi, Jaswinder K.; López, Miguel; Vidal-Puig, Antonio; Medicine, School of MedicineThe epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.Item Author Correction: Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression(Nature, 2020-06-03) Rupaimoole, Rajesha; Wu, Sherry Y.; Pradeep, Sunila; Ivan, Cristina; Pecot, Chad V.; Gharpure, Kshipra M.; Nagaraja, Archana S.; Armaiz-Pena, Guillermo N.; McGuire, Michael; Zand, Behrouz; Dalton, Heather J.; Filant, Justyna; Miller, Justin Bottsford; Lu, Chunhua; Sadaoui, Nouara C.; Mangala, Lingegowda S.; Taylor, Morgan; van den Beucken, Twan; Koch, Elizabeth; Rodriguez-Aguayo, Cristian; Huang, Li; Bar-Eli, Menashe; Wouters, Bradly G.; Radovich, Milan; Ivan, Mircea; Calin, George A.; Zhang, Wei; Lopez-Berestein, Gabriel; Sood, Anil K.; Medicine, School of MedicineThis Article contains an error in Fig. 4. During the preparation of Fig. 4d, the image representing showing E-CADHERIN expression under hypoxia conditions in A2780 cells was inadvertently taken from the image in Supplementary Fig. 15C showing E-CADHERIN expression under hypoxia conditions in SKOV3 cells. The correct version of Fig. 4 is shown below. The error has not been corrected in the PDF or HTML versions of the Article.Item Effects of a checkpoint kinase inhibitor, AZD7762, on tumor suppression and bone remodeling(Spandidos Publications, 2018-09) Wang, Luqi; Wang, Yue; Chen, Andy; Jalali, Aydin; Liu, Shengzhi; Guo, Yunxia; Na, Sungsoo; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyChemotherapy for suppressing tumor growth and metastasis tends to induce various effects on other organs. Using AZD7762, an inhibitor of checkpoint kinase (Chk) 1 and 2, the present study examined its effect on mammary tumor cells in addition to bone cells (osteoclasts, osteoblasts and osteocytes), using monolayer cell cultures and three-dimensional (3D) cell spheroids. The results revealed that AZD7762 blocked the proliferation of 4T1.2 mammary tumor cells and suppressed the development of RAW264.7 pre-osteoclast cells by downregulating nuclear factor of activated T cells cytoplasmic 1. AZD7762 also promoted the mineralization of MC3T3 osteoblast-like cells and 3D bio-printed bone constructs of MLO-A5 osteocyte spheroids. While a Chk1 inhibitor, PD407824, suppressed the proliferation of tumor cells and the differentiation of pre-osteoclasts, its effect on gene expression in osteoblasts was markedly different compared with AZD7762. Western blotting indicated that the stimulating effect of AZD7762 on osteoblast development was associated with the inhibition of Chk2 and the downregulation of cellular tumor antigen p53. The results of the present study indicated that in addition to acting as a tumor suppressor, AZD7762 may prevent bone loss by inhibiting osteoclastogenesis and stimulating osteoblast mineralization.Item Hypoxia Mediated Downregulation of miRNA Biogenesis Promotes Tumor Progression(Nature Publishing Group, 2014-10-29) Rupaimoole, Rajesha; Wu, Sherry Y.; Pradeep, Sunila; Ivan, Cristina; Pecot, Chad V.; Gharpure, Kshipra M.; Nagaraja, Archana S.; Armaiz-Pena, Guillermo N.; McGuire, Michael; Zand, Behrouz; Dalton, Heather J.; Filant, Justyna; Miller, Justin Bottsford; Lu, Chunhua; Sadaoui, Nouara C.; Mangala, Lingegowda S.; Taylor, Morgan; van den Beucken, Twan; Koch, Elizabeth; Rodriguez-Aguayo, Cristian; Huang, Li; Bar-Eli, Menashe; Wouters, Bradly G.; Radovich, Milan; Ivan, Mircea; Calin, George A.; Zhang, Wei; Lopez-Berestein, Gabriel; Sood, Anil K.; Department of Surgery, IU School of MedicineCancer-related deregulation of miRNA biogenesis has been suggested, but the underlying mechanisms remain elusive. Here, we report a previously unrecognized effect of hypoxia in the downregulation of Drosha and Dicer in cancer cells that leads to dysregulation of miRNA biogenesis and increased tumor progression. We show that hypoxia mediated downregulation of Drosha is dependent on ETS1/ELK1 transcription factors. Moreover, mature miRNA array and deep sequencing studies reveal altered miRNA maturation in cells under hypoxic conditions. At a functional level, this phenomenon results in increased cancer progression in vitro and in vivo, and data from patient samples are suggestive of miRNA biogenesis downregulation in hypoxic tumors. Rescue of Drosha by siRNAs targeting ETS1/ELK1 in vivo results in significant tumor regression. These findings provide a new link in the mechanistic understanding of global miRNA downregulation in the tumor microenvironment.