Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

Hubbi, Maimon E.; Gilkes, Daniele M.; Hu, Hongxia; Kshitiz, .; Ahmed, Ishrat; Semenza, Gregg L.

doi:10.1073/pnas.1412840111

Cited by 90 publications

(75 citation statements)

References 57 publications

(64 reference statements)

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“…Recently, an O 2 -independent mechanism of HIF protein degradation has been described involving lysosomes (15)(16)(17)(18). Because an acidic environment is optimal for lysosomal functioning, we focused on this particular non-canonical HIF degradative pathway (37).…”

Section: Resultsmentioning

confidence: 99%

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Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Selfridge¹,

Cavadas

Scholz³

et al. 2016

Journal of Biological Chemistry

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Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-␣ protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O 2 -dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-␣ protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO 2 . Bafilomycin A1, a specific inhibitor of vacuolar-type H ؉ -ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-␣ protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-␣ subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.Current atmospheric CO 2 levels are relatively low when compared with those recorded throughout the natural history of the planet (1). Not surprisingly, therefore, a range of organisms as diverse as bacteria, fungi, plants, and mammals mount physiologic responses to hypercapnia (2). It is now clear that CO 2 , like other physiologic gases such as oxygen and nitric oxide, can be sensed by cells and can elicit adaptive transcriptional responses (2-4).Because O 2 consumption is coupled to CO 2 production, an intimate inverse relationship exists between the levels of these gases in cells and tissues. Furthermore, O 2 and CO 2 levels may become perturbed during certain pathophysiologic states (3, 5). Hypoxia and hypercapnia can co-occur in respiratory disorders such as obstructive sleep apnea syndrome, pneumonia, and chronic obstructive pulmonary disease (6, 7). In acute lung injury hypoxia may arise, whereas permissive hypercapnia is often tolerated as a protective ventilatory strategy in patients presenting with this disorder (8, 9). Hypercapnia and hypoxia also influence inflammatory processes (10 -12). During inflammation, oxygen consumption is significantly elevated, leading to tissue hypoxia. It is likely that this also has consequences for tissue CO 2 levels (3, 11). HIF 8 (which comprises the HIF-1, HIF-2, and HIF-3 isoforms) is the master transcriptional regulator of the cellular response to hypoxia (13). Canonical HIF degradation relies on the activity of O 2 -dependent prolyl hydroxylases 1-3 (14). In normoxia, prolyl hydroxylases enzymatically modify HIF-␣ subunits on proli...

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Section: Resultsmentioning

confidence: 99%

“…HIF regulates the transcription of a host of targets, including those with angiogenic, vasodilatory, inflammatory, and glycolytic functions (13)(14). Recently, evidence has emerged for a separate O 2 -independent, non-canonical HIF degradation pathway that is reliant on chaperone-mediated lysosomal autophagy (15)(16)(17)(18).…”

mentioning

confidence: 99%

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Selfridge¹,

Cavadas

Scholz³

et al. 2016

Journal of Biological Chemistry

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“…The targets of HIFs include genes controlling vascularization, cellular proliferation, migration, and metabolism (6)(7)(8)(9)(10)(11). A wellcharacterized animal model of hypoxia-induced pulmonary hypertension involves exposure to chronic hypoxia (CH), typically 10-12% inspired oxygen.…”

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confidence: 99%

HIF2α–arginase axis is essential for the development of pulmonary hypertension

Cowburn

Crosby

Macías

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

153

158

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Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.A lveolar hypoxia affects vascular flow in the pulmonary vascular bed via an immediate vasoconstrictor response (hypoxic pulmonary vasoconstriction, or HPV) (1). This reduces perfusion of regions of the lung with lowered levels of airflow (2). In conditions including chronic obstructive pulmonary disease (3), idiopathic pulmonary fibrosis (4), and at high altitude (5), HPV probably contributes to persistent increases in pulmonary arterial pressures. This in turn is correlated with reduced plasticity of the vascular bed, sustained pulmonary vascular remodeling, and, ultimately, debilitating right ventricular hypertrophy (RVH) and failure (2).The hypoxia-inducible factors (HIFs) are transcription factors and key regulators of the molecular response to hypoxia. The targets of HIFs include genes controlling vascularization, cellular proliferation, migration, and metabolism (6-11). A wellcharacterized animal model of hypoxia-induced pulmonary hypertension involves exposure to chronic hypoxia (CH), typically 10-12% inspired oxygen. This results in extensive vascular remodeling, marked pulmonary hypertension and RVH over a period of a few weeks. Exposure to CH in rodents results in vasoconstriction and a pattern of vascular remodeling that is reminiscent of humans with hypoxia-associated pulmonary hypertension (12, 13).Mice that are hemizygous for either of the HIF isoforms, HIF-1α (14) or HIF-2α (15), have been shown to have attenuated pulmonary vascular remodeling following experimental CH. Conditional de...

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“…26 Studies demonstrated that cells in hypoxic regions tend to be arrested at G1 phase. 9,27,28 Paclitaxel was found to stabilize cytoplasmic microtubules, thus the cells would stagnate at the beginning of M phase, followed by induction of apoptosis and/or mitotic catastrophe. 29 According to our results, the antiproliferative effect of paclitaxel was attenuated under hypoxia ( Figure 1a), with IC 50 increasing around threefolds.…”

Section: Discussionmentioning

confidence: 99%

Influence of c-Src on hypoxic resistance to paclitaxel in human ovarian cancer cells and reversal of FV-429

Guo

Liao

et al. 2018

Cell Death Dis

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SRC family kinase was documented to have vital roles in adjusting cancer cell malignant behaviors. To date, the role of c-Src, a member of SRC family kinase, in resistance to paclitaxel in human ovarian cancer cells under hypoxia has not been investigated. In the present study, we discovered that hypoxic environment suppressed paclitaxel-induced G2/M phase arrest and blockade of c-Src improved ovarian cancer cells' sensitivity to paclitaxel. FV-429, a derivative of natural flavonoid wogonin, could suppress gene expression and activation of c-Src, followed by deteriorated Stat3 nuclear translocation and its binding to HIF-1α, resulting in paclitaxel resistance reversal through G2/M arrest potentiation. Our study demonstrated that c-Src contributed to hypoxic microenvironment-rendered paclitaxel resistance in human epithelial ovarian cancer cells by G2/M phase arrest deterioration, and through c-Src suppression, FV-429 was capable of reversing the resistance by blocking c-Src/Stat3/HIF-1α pathway. Cell Death and Disease (2018) 8, e3178; doi:10.1038/cddis.2017.367; published online 11 January 2018In solid tumor, cells in hypoxic region becomes resistant to chemotherapy and radiotherapy, the reason for which is that hypoxia helps cancer cells survive by inducing several genes involved that accelerate the progression of malignancy. 1Physiological hypoxia occurs when the oxygen tension falls below 2%, thus a cultivating environment containing 1% oxygen is commonly used to mimic hypoxic environment in vitro.2-5 Ovarian cancer is a common gynecological cancer and one of the lethal cause of death from gynecological malignancy; 6 however, failure or relapse always exists due to the emergence of constant resistance. It has been reported that around 69% ovarian tumors from patients overexpress hypoxia inducible factor-1α (HIF-1α), 7,8 indicating that hypoxia may be closely related to ovarian tumors. Study showed that hypoxia increased G0/G1 phase percentage in ovarian cancer cells.9 However, the effect of paclitaxel is based on the inhibition of microtubule depolymerization, leading to G2/M phase arrest in cancer cells, which can be weakened by the effect induced by hypoxia. Considering on the uncertainty, the resistance to paclitaxel is probably due to G1 phase promotion rendered by hypoxic environment. However, the inner mechanism of the regulation on this cell cycle arrest still remains unclear.Non-receptor tyrosine kinase c-Src seems to be associated with hypoxia.1,10-12 Signal transducer and activator of transcription 3 (Stat3), a transcription factor having vital roles in malignancy, can be activated by c-Src. 13 Mccann et al.14 found that Stat3 activation contributed to hypoxia-induced resistance. Moreover, Huang et al. 9 found that blocking HIF-1α can improve G2/M arrest induced by paclitaxel under hypoxia.Thus we supposed that c-Src/Stat3/HIF-1α axis may regulate hypoxic resistance to paclitaxel under hypoxia.FV-429, a derivative of wogonin, which is one of the main components extracted from Scutellaria baicalensis...

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Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

Cited by 90 publications

References 57 publications

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

HIF2α–arginase axis is essential for the development of pulmonary hypertension

Influence of c-Src on hypoxic resistance to paclitaxel in human ovarian cancer cells and reversal of FV-429

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