Browsing by Subject "HIF-1-ALPHA"

Sort by: Order: Results:

Now showing items 1-6 of 6
  • Lin, Wei Yu; Fordham, Sarah E.; Hungate, Eric; Sunter, Nicola J.; Elstob, Claire; Xu, Yaobo; Park, Catherine; Quante, Anne; Strauch, Konstantin; Gieger, Christian; Skol, Andrew; Rahman, Thahira; Sucheston-Campbell, Lara; Wang, Junke; Hahn, Theresa; Clay-Gilmour, Alyssa I.; Jones, Gail L.; Marr, Helen J.; Jackson, Graham H.; Menne, Tobias; Collin, Mathew; Ivey, Adam; Hills, Robert K.; Burnett, Alan K.; Russell, Nigel H.; Fitzgibbon, Jude; Larson, Richard A.; Le Beau, Michelle M.; Stock, Wendy; Heidenreich, Olaf; Alharbi, Abrar; Allsup, David J.; Houlston, Richard S.; Norden, Jean; Dickinson, Anne M.; Douglas, Elisabeth; Lendrem, Clare; Daly, Ann K.; Palm, Louise; Piechocki, Kim; Jeffries, Sally; Bornhäuser, Martin; Röllig, Christoph; Altmann, Heidi; Ruhnke, Leo; Kunadt, Desiree; Wagenführ, Lisa; Cordell, Heather J.; Darlay, Rebecca; Andersen, Mette K.; Fontana, Maria C.; Martinelli, Giovanni; Marconi, Giovani; Sanz, Miguel A.; Cervera, José; Gómez-Seguí, Inés; Cluzeau, Thomas; Moreilhon, Chimène; Raynaud, Sophie; Sill, Heinz; Voso, Maria Teresa; Lo-Coco, Francesco; Dombret, Hervé; Cheok, Meyling; Preudhomme, Claude; Gale, Rosemary E.; Linch, David; Gaal-Wesinger, Julia; Masszi, Andras; Nowak, Daniel; Hofmann, Wolf Karsten; Gilkes, Amanda; Porkka, Kimmo; Milosevic Feenstra, Jelena D.; Kralovics, Robert; Grimwade, David; Meggendorfer, Manja; Haferlach, Torsten; Krizsán, Szilvia; Bödör, Csaba; Stölzel, Friedrich; Onel, Kenan; Allan, James M. (2021)
    Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 x 10(-8); KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 x 10(-10); HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA). Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.
  • Kim, Christine S.; Ding, Xiaolei; Allmeroth, Kira; Biggs, Leah C.; Kolenc, Olivia I.; L'Hoest, Nina; Chacon-Martinez, Carlos Andres; Edlich-Muth, Christian; Giavalisco, Patrick; Quinn, Kyle P.; Denzel, Martin S.; Eming, Sabine A.; Wickström, Sara A. (2020)
    Stem cells reside in specialized niches that are critical for their function. Upon activation, hair follicle stem cells (HFSCs) exit their niche to generate the outer root sheath (ORS), but a subset of ORS progeny returns to the niche to resume an SC state. Mechanisms of this fate reversibility are unclear. We show that the ability of ORS cells to return to the SC state requires suppression of a metabolic switch from glycolysis to oxidative phosphorylation and glutamine metabolism that occurs during early HFSC lineage progression. HFSC fate reversibility and glutamine metabolism are regulated by the mammalian target of rapamycin complex 2 (mTORC2)-Akt signaling axis within the niche. Deletion of mTORC2 results in a failure to re-establish the HFSC niche, defective hair follicle regeneration, and compromised long-term maintenance of HFSCs. These findings highlight the importance of spatiotemporal control of SC metabolic states in organ homeostasis.
  • Miikkulainen, Petra; Högel, Heidi; Seyednasrollah, Fatemeh; Rantanen, Krista; Elo, Laura L.; Jaakkola, Panu M. (2019)
    Most clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL), resulting in the accumulation of hypoxia-inducible factor -subunits (HIF-) and their downstream targets. HIF-2 expression is particularly high in ccRCC and is associated with increased ccRCC growth and aggressiveness. In the canonical HIF signaling pathway, HIF-prolyl hydroxylase 3 (PHD3) suppresses HIF-2 protein by post-translational hydroxylation under sufficient oxygen availability. Here, using immunoblotting and immunofluorescence staining, qRT-PCR, and siRNA-mediated gene silencing, we show that unlike in the canonical pathway, PHD3 silencing in ccRCC cells leads to down-regulation of HIF-2 protein and mRNA. Depletion of other PHD family members had no effect on HIF-2 expression, and PHD3 knockdown in non-RCC cells resulted in the expected increase in HIF-2 protein expression. Accordingly, PHD3 knockdown decreased HIF-2 target gene expression in ccRCC cells and expression was restored upon forced HIF-2 expression. The effect of PHD3 depletion was pinpointed to HIF2A mRNA stability. In line with these in vitro results, a strong positive correlation of PHD3 and HIF2A mRNA expression in ccRCC tumors was detected. Our results suggest that in contrast to the known negative regulation of HIF-2 in most cell types, high PHD3 expression in ccRCC cells maintains elevated HIF-2 expression and that of its target genes, which may enhance kidney cancer aggressiveness.
  • Ropponen, Jussi O.; Keränen, Mikko A.; Raissadati, Alireza; Nykänen, Antti I.; Krebs, Rainer; Lemstrom, Karl B.; Tikkanen, Jussi M. (2016)
    BACKGROUND: Obliterative bronchiolitis after lung transplantation is characterized by chronic airway inflammation leading to the obliteration of small airways. Hypoxia-inducible factor-1 (HIF-1) is a master regulator of cellular responses to hypoxia and inflammation. The Von Hippel-Lindau protein (pVHL) drives the degradation of oxygen-sensitive subunit HIF-1 alpha that controls the activity of HIF-1. We investigated the effect of myeloid cell targeted gene deletion of HIF-1 alpha or its negative regulator pVHL on the development of obliterative airway disease (OAD) in the recipients of tracheal allografts, a mouse model for obliterative bronchiolitis after lung transplantation. METHODS: Tracheal allografts were heterotopically transplanted from BALB/c donor mice to fully major histocompatibility complex mismatched recipient mice with HIF-1 alpha or VHL gene deletion in myeloid cells. The recipients were left non-immunosuppressed or received tacrolimus daily. Histologic, immunohistochemical, and real-time reverse transcription polymerase chain reaction analyses were performed at 3, 10, and 30 days. RESULTS: In the absence of immunosuppression, myeloid cell-specific VHL deficiency of the recipient mice improved epithelial recovery, decreased inflammatory cell infiltration and expression of pro-inflammatory cytokines, increased regulatory forkhead box P3 messenger RNA expression, and reduced OAD development in tracheal allografts. In the presence of tacrolimus immunosuppression, loss of HIF-1 alpha activity in myeloid cells of the recipient by HIF-1 alpha gene deletion accelerated OAD development in mouse tracheal allografts. CONCLUSIONS: Activity of the HIF-pathway affects the development of allograft rejection, and our results suggest that myeloid cell-specific VHL-deficiency that potentially increases HIF-activity decreases allograft inflammation and the subsequent development of OAD in mouse tracheal allografts. (C) 2016 International Society for Heart and Lung Transplantation. All rights reserved.
  • Kozlova, Nina; Mennerich, Daniela; Samoylenko, Anatoly; Dimova, Elitsa Y.; Koivunen, Peppi; Biterova, Ekaterina; Richter, Kati; Hassinen, Antti; Kellokumpu, Sakari; Manninen, Aki; Miinalainen, Ilkka; Glumoff, Virpi; Ruddock, Lloyd; Drobot, Lyudmyla Borysivna; Kietzmann, Thomas (2019)
    The EGFR adaptor protein, CIN85, has been shown to promote breast cancer malignancy and hypoxia-inducible factor (HIF) stability. However, the mechanisms underlying cancer promotion remain ill defined. Here we show that CIN85 is a novel binding partner of the main HIF-prolyl hydroxylase, PHD2, but not of PHD1 or PHD3. Mechanistically, the N-terminal SRC homology 3 domains of CIN85 interacted with the proline-arginine-rich region within the N-terminus of PHD2, thereby inhibiting PHD2 activity and HIF degradation. This activity is essential in vivo, as specific loss of the CIN85-PHD2 interaction in CRISPR/Cas9-edited cells affected growth and migration properties, as well as tumor growth in mice. Overall, we discovered a previously unrecognized tumor growth checkpoint that is regulated by CIN85-PHD2 and uncovered an essential survival function in tumor cells by linking growth factor adaptors with hypoxia signaling. Significance: This study provides unprecedented evidence for an oxygen-independent mechanism of PHD2 regulation that has important implications in cancer cell survival.
  • Metsälä, Olli; Kreutzer, Joose; Högel, Heidi; Miikkulainen, Petra; Kallio, Pasi; Jaakkola, Panu M. (2018)
    BackgroundCells in solid tumours are variably hypoxic and hence resistant to radiotherapy - the essential role of oxygen in the efficiency of irradiation has been acknowledged for decades. However, the currently available methods for performing hypoxic experiments in vitro have several limitations, such as a limited amount of parallel experiments, incapability of keeping stable growth conditions and dependence on CO2 incubator or a hypoxia workstation. The purpose of this study was to evaluate the usability of a novel portable system (Minihypoxy) in performing in vitro irradiation studies under hypoxia, and present supporting biological data.Materials and methodsThis study was conducted on cancer cell cultures in vitro. The cells were cultured in normoxic (similar to 21% O-2) or in hypoxic (1% O-2) conditions either in conventional hypoxia workstation or in the Minihypoxy system and irradiated at dose rate 1.28Gy/min2.9%. The control samples were sham irradiated. To study the effects of hypoxia and irradiation on cell viability and DNA damage, western blotting, immunostainings and clonogenic assay were used. The oxygen level, pH, evaporation rate and osmolarity of the culturing media on cell cultures in different conditions were followed.ResultsThe oxygen concentration in interest (5, 1 or 0% O-2) was maintained inside the individual culturing chambers of the Minihypoxy system also during the irradiation. The radiosensitivity of the cells cultured in Minihypoxy chambers was declined measured as lower phosphorylation rate of H2A.X and increased clonogenic capacity compared to controls (OER similar to 3).Conclusions The Minihypoxy system allows continuous control of hypoxic environment in multiple wells and is transportable. Furthermore, the system maintains the low oxygen environment inside the individual culturing chambers during the transportation and irradiation in experiments which are typically conducted in separate facilities.