Professor of Molecular Physiology and Pathology
Wellcome Trust Principal Research Fellow
Fellow of Pembroke College
Randall Johnson is accepting applications for PhD students.
I received a Bachelor of Science in Molecular Biology and a Bachelor of Arts in Swedish Language and Literature concurrently in 1983 from the University of Washington, in Seattle. Having resolved to choose science over literature, I worked for a couple of years as a research technician for Dr. Don Pious at the UW, on a project concerned with the genetics of the human major histocompatibility complex. I then went to Harvard to do my doctoral work with Prof. Bruce Spiegelman, where we were involved in the early days of gene targeting in embryonic stem cells; and I knocked out the c-fos and c-jun proto-oncogenes, amongst others, while receiving a Ph.D. in Genetics. I did my post-doctoral work as a Jane Coffin Childs Fellow with Prof. Doug Hanahan when he was at UC San Francisco, working on the role of angiogenesis in transgenic tumor models. I began my career as a group leader in the Dept. of Biology at the University of California, San Diego. There, our lab began our study of hypoxia and its effects on tumorigenesis and physiology, continuing to use knockout and other genetic models. In 2011, I came to Cambridge and the Dept. of PDN as a Wellcome Trust Principal Research Fellow. In 2012 I became an associated member of the Department of Cell and Molecular Biology of the Karolinska Institute, in Stockholm, Sweden, and I continue to be an adjunct member of the Division of Biological Sciences at UC San Diego.
We work on how the body responds to hypoxia, or low levels of tissue oxygen. This is relevant to a number of diseases, including cancer, and the laboratory is interested in hypoxic response in disease as well as in normal physiology.
- The response to hypoxia acts in significant part through the Hypoxia Inducible Factor, or HIF. The actions of this transcription factor are evident in almost all forms of cancer, but HIF is also present in other disease states. Further, many aspects of normal physiological response include activation of HIF: HIF expression is seen in normal embryonic development, it is seen whenever wound healing or inflammation occur, and is essential for adjustment to high altitude or whenever the organism experiences a lower than normal level of oxygen.
- Cancer: our work has for many years focussed on how malignant cells and the tissues that surround and infiltrate them react to oxygen levels. The levels of oxygen found vary tremendously both from cancer to cancer, and within individual tumors. One of the key findings from our recent work has been that each cell type found within tumors utilizes the HIF response differently; the malignant cells, tumor-associated fibroblasts, myeloid cells, endothelial cells and lymphoid cells all have different spectra of response via HIF, and these differences impact how tumors grow, survive and, ultimately, metastasize.
- Inflammation, infection and immunity: We have investigated how T cells and macrophages utilize hypoxic response to allow immune response. We are actively investigating this in terms of models of infection, inflammation, and immunological response to cancer; and we are also asking how myeloid/lymphoid interactions are affected by the response to oxygenation.
- Physiology: a critical aspect of ventilatory control is the normative response of the carotid body and other tissues to the organisms overall oxygenation. This response in turn can affect various aspects of homeostasis, including pulmonary vascular tension and even systemic blood pressure. We have found that this control is highly related to the function of HIF and hypoxic response, in a way that is tightly controlled by complex interactions amongst tissue types.
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
Yamamoto H, Rundqvist H, Branco C, and Johnson RS. (2016) Autocrine VEGF isoforms differentially regulate endothelial cell behavior. Frontiers in Cell and Developmental Biology 4:99
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
Johnson RS, Titze J, and Weller R. (2016) Cutaneous control of blood pressure. Current Opinion Nephrology and Hypertension 25:11-15
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 Cardiomyocytes. Developmental 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 heart. Journal 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