The purpose of the HIF-1/PHD feedback loop: to limit mTOR-induced HIF-1alpha. Zoya N Demidenko
The purpose of the HIF-1/PHD feedback loop: to limit mTOR-induced HIF-1alpha
Abstract
Prolyl hydroxylases (PHDs) target hypoxia-inducible factor-1α (HIF-1α) for degradation. Hypoxia inactivates PHDs, causing accumulation of HIF-1α. In turn, HIF-1 further transactivates PHDs. It is thought that the purpose of this feedback loop is to limit HIF-1α accumulation caused by hypoxia. Here, we suggest that the feedback is intended to limit the induction of HIF-1α by insulin, growth factors, hormones, cytokines and nutrients. These stimuli induce HIF-1α by increasing its translation, not by inhibiting PHDs. As exemplified herein, in a mTOR-dependent manner, insulin transiently induced HIF-1α in retinal pigment epithelial (RPE) cells. Induction of HIF-1α was followed by activation of HIF-dependent transcription. Furthermore, DFX, which inactivates PHDs, potentiated the induction of HIF-1α by insulin. We propose that the most relevant function of the PHD-HIF feedback loop is to limit the induction of HIF-1α by mTOR. The failure to limit mTOR-dependent induction of HIF-1 may contribute to age-related macular degeneration and diabetic retinopathy, suggesting rapamycin for prevention of these age-related diseases.
oncotarget impact factor 2021 Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executive Manager of the Oncotarget journal . Oncotarget publishes high-impact research papers of general interest and outstanding significance and novelty in all areas of biology and medicine: in translational, basic and clinical research including but not limited to cancer research, oncogenes, oncoproteins and tumor suppressors, signaling pathways as potential targets for therapeutic intervention, shared targets in different diseases (cancer, benign tumors, atherosclerosis, eukaryotic infections, metabolic syndrome and other age-related diseases), chemotherapy, and new therapeutic strategies. After earning her Ph.D. in molecular biology, Zoya was awarded a Fogarty post-doctoral Fellowship from the National Institutes of Health in Bethesda, MD. After successful completion of post-doctoral training, she continued her professional career at George Washington University and Albert Einstein School of Medicine . In 2005 she cofounded the startup company Oncotarget Inc. which is focused on the development of anti-aging and anti-cancer drugs. Her research interests include signal transduction, cell cycle and cellular senescence, and their pharmacological targeting. In 2009 she cofounded the publishing house Impact Journals which specializes in publishing scientific journals. In 2011 she was selected to be a Member of the National Association of Professional Women .
When public mention modern medicine, precision plays one of the most significant roles and people’s lives are literally dependent on it. Likewise, any researches pertaining to medicine are required to comply with the top standards. The problem today is that any results of researches can be published online and used as a reference without being properly verified and validated. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this issue and decided to create an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been founded back in 2010. The major principle of this journal is related to Altmetric scores that are used as a quality indicator. That allows both readers and authors to verify publications with Altmetric Article Reports that create “real-time feedback containing data summary related to a particular publication.” Oncotarget website provides a full publications list with respective scores higher than 100 as well as reports discussed previously. Mikhail (Misha) Blagosklonny glad to share his new approach and hopes it provides the necessary assistance to anybody, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This article was published back in 2018 by Oncotarget and written by several experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study mentions that “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and provides an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
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Another Oncotarget’s study with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This study has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have seen a short overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do receive useful scientific facts. Oncotarget is proud to have the chance to share with online customers this highly appreciated and high-quality information, that is trustworthy and reliable.
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