Beyond hypoxia-inducible factors: New Molecules Interacting in Hypoxia-Signaling and Metabolism

A limited supply of oxygen (hypoxia) has profound effects on both cellular and whole body function and contributes to the pathogenesis of diabetes mellitus, atherosclerosis, thrombosis, pulmonary hypertension and tumorigenesis.

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Project funder

Biocenter Oulu

Project coordinator

University of Oulu

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Project description

Hypoxia-inducible transcription factors (HIFs) contribute to these processes and our work on oxygen signaling and metabolism has revealed mechanistic details on how HIFs respond not only to hypoxia but also to reactive oxygen species (ROS) and several “non-oxygen” signals such as insulin, or cytokines generated by various enzymes in different cellular compartments. While HIFs have been extensively studied as key mediators of the hypoxic response, a myriad of additional molecules appear to actively participate in hypoxia signaling and metabolic adaptations beyond HIFs. However, whether, and how, these molecules integrate into the above mentioned mechanisms is as yet unknown. This will be clarified in the present project. From non-coding RNAs and epigenetic modifiers to novel proteins and metabolic regulators, we delve into the diverse landscape of molecules influencing hypoxia-induced pathways. Furthermore, we explore the intricate crosstalk between these emerging players, shedding light on their interplay within the intricate network governing cellular responses to low oxygen environments. As we unravel the complexities of hypoxia signaling, these insights offer promising avenues for the development of targeted therapeutic strategies in various pathological conditions associated with oxygen deprivation.

Key publications

Richter K, Paakkola T, Mennerich D, Kubaichuk K, Konzack A, Kippari HA, Kozlova N, Koivunen P, Haapasaari KM, Jukkola-Vuorinen A, Teppo HR, Dimova EY, Bloigu R, Szabo Z, Kerkelä R, Kietzmann T. USP28 Deficiency Promotes Breast and Liver Carcinogenesis as well as Tumor Angiogenesis in a HIF-independent Manner. Mol Cancer Res. (2018) 16:1000-1012 doi: 10.1158/1541-7786.MCR-17-0452

Kozlova N, Mennerich D, Samoylenko A, Dimova EY, Koivunen P, Biterova E, Richter K, Hassinen A, Kellokumpu S, Manninen A, Miinalainen A, Glumoff V, Ruddock L, Drobot L, Kietzmann T. The pro-oncogenic adaptor CIN85 inhibits hypoxia-inducible factor prolyl hydroxylase-2. Cancer Res (2019) 79(16):4042-4056;

Dimova, EY. Jakupovic M, Kubaichuk K, MennerichD, Chi TF, Tamanini F Oklejewicz M, Hänig, J, Byts N, Mäkelä K, Herzig, KH, Koivunen P, Chaves I, Van der Horst G, Kietzmann T. The Circadian Clock Protein CRY1 Is a Negative Regulator of HIF-1α. Cell Rep (2018) iScience. 2019 Mar 29;13:284-304. doi: 10.1016/j.isci.2019.02.027

Deschoemaeker S, Di Conza G, Lilla S, Martín-Pérez R, Mennerich D, Boon L, Hendrikx S, Maddocks OD, Marx C, Radhakrishnan P, Prenen H, Schneider M, Myllyharju J, Kietzmann T, Vousden KH, Zanivan S, Mazzone M. PHD1 regulates p53-mediated colorectal cancer chemoresistance. EMBO Mol Med (2015). 7:1350-65.

Konzack A, Jakupovic M, Kubaichuk K, Görlach A, Dombrowski F, Miinalainen I, Sormunen R, Kietzmann T. Mitochondrial Dysfunction Due to Lack of Manganese Superoxide Dismutase Promotes Hepatocarcinogenesis. Antioxid Redox Signal. (2015) Nov 10;23(14):1059-75. doi: 10.1089/ars.2015.6318..

Flügel D, Görlach A, Kietzmann T. GSK-3β regulates cell growth, migration, and angiogenesis via Fbw7 and USP28-dependent degradation of HIF-1α. Blood. (2012) 119(5):1292-301. doi: 10.1182/blood-2011-08-375014.

Diebold I, Flügel D, Becht S, Belaiba RS, Bonello S, Hess J, Kietzmann T, Görlach A. The hypoxia-inducible factor-2alpha is stabilized by oxidative stress involving NOX4. Antioxid Redox Signal. (2010) Aug 15;13(4):425-36. doi:10.1089/ars.2009.3014.

Flügel D, Görlach A, Michiels C, Kietzmann T. Glycogen synthase kinase 3phosphorylates hypoxia-inducible factor 1alpha and mediates its destabilizationin a VHL-independent manner. Mol Cell Biol. (2007) May;27(9):3253-65. doi: 10.1128/MCB.00015-07

Liu Q, Möller U, Flügel D, Kietzmann T. Induction of plasminogen activatorinhibitor I gene expression by intracellular calcium via hypoxia-inducible factor-1. Blood. (2004) Dec 15;104(13):3993-4001. doi:10.1182/blood-2004-03-1017

Liu Q, Berchner-Pfannschmidt U, Möller U, Brecht M, Wotzlaw C, Acker H, Jungermann K, Kietzmann T. A Fenton reaction at the endoplasmic reticulum isinvolved in the redox control of hypoxia-inducible gene expression. Proc NatlAcad Sci U S A. (2004) Mar 23;101(12):4302-7. doi: 10.1073/pnas.0400265101.