Int J Stem Cells.  2019 Mar;12(1):8-20. 10.15283/ijsc18109.

Role of HIF1α Regulatory Factors in Stem Cells

Affiliations
  • 1Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, Korea. hjhan@snu.ac.kr

Abstract

Hypoxia-inducible factor 1 (HIF1) is a master transcription factor that induces the transcription of genes involved in the metabolism and behavior of stem cells. HIF1-mediated adaptation to hypoxia is required to maintain the pluripotency and survival of stem cells under hypoxic conditions. HIF1 activity is well known to be tightly controlled by the alpha subunit of HIF1 (HIF1α). Understanding the regulatory mechanisms that control HIF1 activity in stem cells will provide novel insights into stem cell biology under hypoxia. Recent research has unraveled the mechanistic details of HIF1α regulating processes, suggesting new strategies for regulating stem cells. This review summarizes recent experimental studies on the role of several regulatory factors (including calcium, 2-oxoglutarate-dependent dioxygenase, microtubule network, importin, and coactivators) in regulating HIF1α activity in stem cells.

Keyword

Stem cells; Hypoxia-inducible factor 1 alpha (HIF1α); Calcium; 2-Oxoglutrate-dependent dioxygenase (2OGDD); Microtubule; Importin

MeSH Terms

Anoxia
Biology
Calcium
Hypoxia-Inducible Factor 1
Karyopherins
Metabolism
Microtubules
Stem Cells*
Transcription Factors
Calcium
Hypoxia-Inducible Factor 1
Karyopherins
Transcription Factors

Figure

  • Fig. 1 Schematic structures of HIF1α and HIF1β domains. Both HIF1α and HIF1β possess bHLH and PAS domains for the formation of heterodimeric complexes and for DNA binding. HIF1α has two transactivation domains (NTAD and CTAD) and an inhibitory domain (ID), whereas HIF1β possesses only the CTAD domain. PHD hydroxylases possess two proline residues (P402 and P564) in the NTAD domain, whereas FIH hydroxylases possess an asparagine residue (N803) in the CTAD domain in HIF1α. These hydroxylated residues are ubiquitinated by VHL.

  • Fig. 2 Regulatory mechanism of calcium on HIF1α induction. Calcium channels regulating intracellular calcium levels induce HIF1α expression by inducing gene transcription, translation, and stabilization. STIM1, MCU, and TRPM2-activated intracellular calcium signaling increase HIF1A mRNA expression. TRPM2 and TRPC1 activate the Akt/mTORC1 pathway, which increases HIF1α translation. TRPM8 and TRPC6 stabilize HIF1α via the calcineurin/RACK pathway and by PHD-mediated prolyl hydroxylation, respectively.

  • Fig. 3 Regulatory factors of 2OGDDs for HIF1α stabilization. Succinate, fumarate, and mitochondrial ROS inhibit PHD activation, leading to HIF1α stability. Conversely, 2OG, Fe2+, and ascorbate are required for PHD activation, followed by VHL-induced HIF1α ubiquitination. FIH is more sensitive to oxygen than VHL. Like PHD, ascorbate also activates FIH, which leads to asparaginyl hydroxylation, leading in turn to the destabilization of HIF1α.

  • Fig. 4 Roles of microtubule network, importin, and coactivators in the nuclear translocation and activation of gene transcription in HIF1α. HIF1α nuclear translocation is regulated by microtubule stability and dynein activation. Interaction between HIF1α and importins α3 and α7 is important for the import of HIF1α into the cell nucleus. Dynein adaptor proteins (including BICD) may regulate the dynein-associated nuclear translocation of HIF1α. CBP/p300, Tip60, CDK8, PKM2, and PHD3 bind to HIF1α to coactivate gene transcription. Other gene transcription factors, such as STAT3 and AHR, also interact with HIF1α by synergistically activating HIF1-target genes expression.


Reference

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