Randall Johnson's Group

Our laboratory uses genetic models to study the effects of hypoxia in physiological and pathological contexts, specifically dissecting the roles of different isoforms of Hypoxia Inducible Factors (HIF) as regulators of the hypoxia response in different cell types.

One of the functions of the mammalian hypoxic response in development and cancer is the generation of nascent vascular networks through angiogenesis. Through transcriptional regulation of the vascular endothelial growth factor A (VEGF-A) and other angiogenic factors, the Hypoxia-Inducible Factors can increase angiogenesis in an oxygen dependent fashion, and gives a survival and growth advantage to HIF wild type tumors. However, their role in other cell types is not always redundant. We are starting to understand that each cell type within the tumor microenvironment has specific hypoxia response strategies that independently affect tumor growth and tumor dispersion. We use genetic techniques to identify the role of hypoxia-triggered and HIF-dependent responses in different cell types, with a particular focus on cancer.

Group members

Milos GojkovicPhD student, Graduate Student
Michael GrallaPhD student
Randall JohnsonProfessor
Helene RundqvistSenior lab manager
Pedro VelicaSenior lab manager
Nikola VojnovicPhD student

Selected publications

Tyrakis P, Palazon A, Macias D,  Kian LL, Phan AT, Veliça P, You J, Chia GS, Sim J, Doedens A, Abelanet A, Evans CE, Griffiths JR, Poellinger L, Goldrath AW and Johnson RS. (2016) S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate.  Nature 540:236-241

Phan AT, Doedens AL, Palazon A, Tyrakis PA, Cheung KP, Johnson RS, Goldrath AW. (2016) Constitutive Glycolytic Metabolism Supports CD8+ T Cell Effector Memory Differentiation during Viral Infection.  Immunity 45(5):1024-1037

Cowburn AS, Crosby A, Macias D, Branco C, Colaço R, Southwood M, Toshner M, Crotty Alexander L, Morrell N, Chilvers ER, and Johnson RS. (2016) HIF2α-arginase axis is essential for the development of pulmonary hypertension.  Proceedings of the National Academy of Sciences 113 (31), 8801-8806

Evans CE, Bendahl PO, Belting M, Branco C, Johnson RS. (2016) Diverse roles of cell-specific hypoxia-inducible factor 1 in cancer-associated hypercoagulation. Blood 127(10):1355-60.

Bleymehl K, Pérez-Gómez A, Omura M, Moreno-Pérez A, Macías D, Bai Z, Johnson RS, Leinders-Zufall T, Zufall F, and Mombaerts P. (2016) A Sensor for Low Environmental Oxygen in the Mouse Main Olfactory Epithelium. Neuron 92:1196-1203

Guimarães-Camboa N, Stowe J, Aneas I, Sakabe N, Cattaneo P, Henderson L, Kilberg MS, Johnson RS, Chen J, McCulloch AD, Nobrega MA, Evans SM, Zambon AC (2015). HIF1α Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal CardiomyocytesDevelopmental Cell 33(5):507-21

Koh HS, Chang CY, Jeon SB, Yoon HJ, Ahn YH, Kim HS, Kim IH, Jeon SH, Johnson RS, Park EJ (2015). The HIF-1/glial TIM-3 axis controls inflammation-associated brain damage under hypoxia. Nature Communications 6:6340

Ashmore T, Fernandez BO, Evans CE, Huang Y, Branco-Price C, Griffin JL, Johnson RS, Feelisch M, Murray AJ. (2015) Suppression of erythropoiesis by dietary nitrate. FASEB Journal 29(3):1102-1112

Ashmore T, Fernandez BO, Branco-Price C, West JA, Cowburn AS, Heather LC, Griffin JL, Johnson RS, Feelisch M, Murray AJ. (2014) Dietary nitrate increases arginine availability and protects mitochondrial complex I and energetics in the hypoxic rat heartJournal of Physiology 592(Pt 21):4715-4731

Palazon A, Goldrath AW, Nizet V, Johnson RS, (2014), HIF transcription factors, inflammation, and immunity, Immunity, 41(4):518-28

Lee YS, Kim JW, Osborne O, Oh da Y, Sasik R, Schenk S, Chen A, Chung H, Murphy A, Watkins SM, Quehenberger O, Johnson RS, Olefsky JM (2014), Increased Adipocyte O2 Consumption Triggers HIF-1α, Causing Inflammation and Insulin Resistance in Obesity, Cell, 157:1339-1352

Cowburn AS, Takeda N, Boutin AT, Kim J, Sterling J, Nakasaki M, Southwood M, Goldrath AW, Jamora C, Nizet V, Chilvers E, Johnson RS (2013), Differential regulation of systemic arterial pressure by the skin: role of HIF isoforms, Proceedings of the National Academy of Sciences, 110:17570-17575

Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, Johnson RS, Goldrath AW, (2013), Hypoxia inducible factors enhance CD8+ T cell effector responses to persistent antigen, Nature Immunology, 14:1173-1182

Kim J, Evans C, Weidemann A, Takeda N, Lee YS, Stockmann C, Branco-Price C, Brandberg F, Leone G, Ostrowski MC, Johnson RS, (2012), Loss of Fibroblast HIF-1a accelerates tumorigenesis, Cancer Research, 72:3187-3195

Branco-Price C, Zhang N, Schnelle M, Evans C, Katschinski DM, Liao D, Ellies L, Johnson RS, (2012), Endothelial cell HIF-1a and HIF-2a differentially regulate metastatic success, Cancer Cell, 21:52-65

Doedens A, Stockmann C, Rubinstein M, Liao D, Zhang N, DeNardo D, Coussens LM, Karin M, Goldrath A, Johnson RS, (2010), Macrophage expression of HIF-1 suppresses T cell function and promotes tumor progression, Cancer Research, 70:7465-7475

Zhang N, Fu Z, Linke S, Chicher J, Gorman JJ, Poellinger L, Peet DJ, Powell F, Johnson RS, (2010), The asparaginyl hydroxylase FIH is an essential regulator of metabolism, Cell Metabolism, 11:364-378

Takeda N, O’Dea EL, Doedens A, Kim J-W, Weidemann A, Stockmann C, Asagiri M, Simon MC, Hoffmann A, Johnson RS, (2010), Differential activation and antagonistic function of HIF-a isoforms in macrophages are essential for NO homeostasis, Genes and Development, 24:491-501

Stockmann C, Kerdiles Y, Nomaksteinsky M, Weidemann A, Takeda N, Doedens A, Torres-Collado AX, Iruela-Arispe L, Nizet V, Johnson RS, (2010), Loss of myeloid cell-derived growth factor accelerates fibrosis, Proceedings of the National Academy of Sciences, 107:4329-4334

Nizet V, Johnson RS, (2009), Interdependence of hypoxic and innate immune responses, Nature Reviews Immunology, 9:609-617

Stockmann C, Doedens A, Weidemann A, Zhang N, Greenberg J, Cheresh D, Johnson RS, (2008), Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis, Nature, 456:814-818

Boutin A, Weidemann A, Fu Z, Mesropian L, Gradin K, Jamora C, Wiesener M, Eckardt K-U, Koch CJ, Ellies LG, Haddad G, Haase VH, Simon MC, Poellinger L, Powell FL, Johnson RS, (2008), Epidermal sensing of oxygen is essential for systemic hypoxic response, Cell, 133:223-234

Mason S, Ameln H, Duh R, McNulty WJ, Howlett RA, Olfert IM, Sundberg CJ, Poellinger L, Johnson RS, (2007), HIF-1α in endurance training: suppression of oxidative metabolism, American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 293:R2059-206

Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, Johnson RS, (2007), Regulation of iron homeostasis by the hypoxia inducible transcription factors (HIFs), Journal of Clinical Investigation, 117:1926-1932

Liao D, Corle C, Seagroves TN, Johnson RS, (2007), HIF-1α is a key regulator of metastasis in a transgenic model of cancer initiation and progression, Cancer Research, 67:563-572

 

Cell Biology