ArticlePloS one2021
The regulation of Hypoxia-Inducible Factor-1 (HIF-1alpha) expression by Protein Disulfide Isomerase (PDI).
Article in PloS one, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- BIP orchestrates bidirectional ER protein trafficking via co-chaperone complexes.Cellular & molecular biology letters · 2026Article
- Endoplasmic Reticulum Redoxome: Protein Folding and Beyond.Biochemistry · 2026Review
- Spatial protein redistribution: wandering but not lost.Cellular and molecular life sciences : CMLS · 2025Review
- Less is better: various means to reduce protein load in the endoplasmic reticulum.The FEBS journal · 2025Review
- Exploring the Role of Hypoxia and HIF-1α in the Intersection of Type 2 Diabetes Mellitus and Endometrial Cancer.Current oncology (Toronto, Ont.) · 2025Review
- SPATA20 deficiency enhances the metastatic and angiogenic potential of cancer cells by promoting HIF-1α synthesis.American journal of cancer research · 2024Article
- Novel genetic regulators of fibrinogen synthesis identified by an in vitro experimental platform.Journal of thrombosis and haemostasis : JTH · 2023Article
- The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression.Scientific reports · 2022Article
- Functions and mechanisms of protein disulfide isomerase family in cancer emergence.Cell & bioscience · 2022Review
- Roles of Protein Disulfide Isomerase in Breast Cancer.Cancers · 2022Review
- Can thiol-based redox systems be utilized as parts for synthetic biology applications?Redox report : communications in free radical research · 2021Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor, plays a critical role in adaption to hypoxia, which is a major feature of diseases, including cancer. Protein disulfide isomerase (PDI) is up-regulated in numerous cancers and leads to cancer progression. PDI, a member of the TRX superfamily, regulates the transcriptional activities of several transcription factors. To investigate the mechanisms by which PDI affects the function of HIF-1alpha, the overexpression or knockdown of PDI was performed. The overexpression of PDI decreased HIF-1alpha expression in the human hepatocarcinoma cell line, Hep3B, whereas the knockdown of endogenous PDI increased its expression. NH4Cl inhibited the decrease in HIF-1alpha expression by PDI overexpression, suggesting that HIF-1alpha was degraded by the lysosomal pathway. HIF-1alpha is transferred to lysosomal membranes by heat shock cognate 70 kDa protein (HSC70). The knockdown of HSC70 abolished the decrease, and PDI facilitated the interaction between HIF-1alpha and HSC70. HIF-1alpha directly interacted with PDI. PDI exists not only in the endoplasmic reticulum (ER), but also in the cytosol. Hypoxia increased cytosolic PDI. We also investigated changes in the redox state of HIF-1alpha using PEG-maleimide, which binds to thiols synthesized from disulfide bonds by reduction. An up-shift in the HIF-1alpha band by the overexpression of PDI was detected, suggesting that PDI formed disulfide bond in HIF-1alpha. HIF-1alpha oxidized by PDI was not degraded in HSC70-knockdown cells, indicating that the formation of disulfide bond in HIF-1alpha was important for decreases in HIF-1alpha expression. To the best of our knowledge, this is the first study to show the regulation of the expression and redox state of HIF-1alpha by PDI. We also demonstrated that PDI formed disulfide bonds in HIF-1alpha 1-245 aa and decreased its expression. In conclusion, the present results showed that PDI is a novel factor regulating HIF-1alpha through lysosome-dependent degradation by changes in its redox state.
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