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Review
. 2016 Feb;117(2):267-78.
doi: 10.1002/jcb.25283.

Hypoxia-Inducible Factor-1: A Critical Player in the Survival Strategy of Stressed Cells

Shuyang Chen  1 , Nianli Sang  1   2   3
Affiliations
Review

Hypoxia-Inducible Factor-1: A Critical Player in the Survival Strategy of Stressed Cells

Shuyang Chen et al. J Cell Biochem. 2016 Feb.

Abstract

HIF-1 activation has been well known as an adaptive strategy to hypoxia. Recently it became clear that hypoxia was often accompanied by insufficient supply of glucose or amino acids as a common result of poor circulation that frequently occurs in solid tumors and ischemic lesions, creating a mixed nutrient insufficiency. In response to nutrient insufficiency, stressed cells elicit survival strategies including activation of AMPK and HIF-1 to cope with the stress. Particularly, in solid tumors, HIF-1 promotes cell survival and migration, stimulates angiogenesis, and induces resistance to radiation and chemotherapy. Interestingly, radiation and some chemotherapeutics are reported to trigger the activation of AMPK. Here we discuss the recent advances that may potentially link the stress responsive mechanisms including AMPK activation, ATF4 activation and the enhancement of Hsp70/Hsp90 function to HIF-1 activation. Potential implication and application of the stress-facilitated HIF-1 activation in solid tumors and ischemic disorders will be discussed. A better understanding of HIF-1 activation in cells exposed to stresses is expected to facilitate the design of therapeutic approaches that specifically modulate cell survival strategy.

Keywords: AMPK; HDAC4; HDAC5; HIF-1; HYPOXIA; Hsp70; Hsp90; STRESS RESPONSE.

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Figures

Figure 1
Figure 1. Summary of the synthesis, posttranslational processing and hypoxia-controlled degradation of HIF-1α
After translation, nascent HIF-1α interacts with the molecule chaperone Hsp70/Hsp90 system for processing and maturation. Proteins fail the posttranslational folding processes will be degraded by a quality control system using a ubiquitination-independent proteasome degradation pathway (UIP). The protein levels of correctly folded functional HIF-1α will be regulated by the oxygen-dependent hydroxylation-ubiquitination mechanism.
Figure 2
Figure 2. Schematic structure of HIF-1α and the conventional oxygen-dependent inhibition of HIF-1
Figure 3
Figure 3. Signaling pathways that controls the rate of HIF-1α translation
Activation of oncogenes or loss of tumor suppressors promotes HIF-1α translation, which is suppressed by mTOR inhibition.
Figure 4
Figure 4. Proposed model of AMPK-HDAC5 enhanced, Hsp70/Hsp90 executed posttranslational processing of HIF-1α
AMPK serves as a sensor of multiple types of stresses, which promotes the cytosolic localization of HDAC4 and HDAC5, depending on which is expressed in a specific type of cells. HDAC4 and HDAC5 catalyzed deacetylation of Hsp70 enhances the efficiency of posttranslational processing of HIF-1α, minimizing the pre-mature degradation.
Figure 5
Figure 5. Cytosolic HDAC4 and HDAC5 contribute to hypoxic stabilization of HIF-1α and functional activation of HIF-1
Knockdown of either HDAC4 or HDAC5 attenuates hypoxia triggered HIF-1α accumulation. Hep3B cells were transfected with indicated siRNA . After 42 h, cells were exposed to hypoxia (1% O2) for 6 h. (A) Western blotting showing the protein levels of HIF-1α, HDAC4 and HDAC5. The protein levels of α-tubulin were determined as a loading control. Note that hypoxia enhanced HDAC5 but not HDAC4. (B) Total RNA was collected, and quantitative real time PCR was performed following reverse transcription to determine the mRNA levels of CA-IX as an indicator of HIF-1 function. (C) Cytosolic HDAC4 mutant (S265/266A) is sufficient to stabilize HIF-1α. Hep3B cells were cotransfected with 2 µg of HA-HIF-1α together with 2 µg of either control vector, Flag-HDAC4(WT), or cytosolic mutant HDAC4-S265/266A. HIF-1α and Flag-tagged HDAC4 were detected by Western blotting.
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