Pro-apoptotic activity of inhibitory PAS domain protein (IPAS), a negative regulator of HIF-1, through binding to pro-survival Bcl-2 family proteins

Torii, Satoru; Goto, Yuhei; Ishizawa, Toshiyuki; Hoshi, Hajime; Goryo, Kenji; Yasumoto, Ken Ichi; Fukumura, Hiroshi; Sogawa, Kazuhiro

doi:10.1038/cdd.2011.47

Cited by 32 publications

(52 citation statements)

References 31 publications

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“…This is consistent with recent in vitro studies reporting that IPAS had proapoptotic activity and induced mitochondria depolarization and caspase-3 activation in rat PC12 cells (48). IPAS acted in mitochondria by directly binding to Bcl-x(L) and other prosurvival proteins (48).…”

Section: Biological Function(s) Of Hif-3␣ Variantssupporting

confidence: 81%

“…Interestingly, overexpression of stabilized Hif-3␣ in zebrafish not only resulted in growth and developmental retardation, but also caused morphological abnormalities (56). This is consistent with recent in vitro studies reporting that IPAS had proapoptotic activity and induced mitochondria depolarization and caspase-3 activation in rat PC12 cells (48). IPAS acted in mitochondria by directly binding to Bcl-x(L) and other prosurvival proteins (48).…”

Section: Biological Function(s) Of Hif-3␣ Variantssupporting

confidence: 77%

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Hypoxia-inducible factor 3 biology: complexities and emerging themes

Duan

2016

American Journal of Physiology-Cell Physiology

203

172

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Duan C. Hypoxia-inducible factor 3 biology: complexities and emerging themes. Am J Physiol Cell Physiol 310: C260 -C269, 2016. doi:10.1152/ajpcell.00315.2015.-The hypoxia-inducible factor (HIF) family has three distinct members in most vertebrates. All three HIFs consist of a unique and oxygen-labile ␣-subunit and a common and stable ␤-subunit. While HIF-1 and HIF-2 function as master regulators of the transcriptional response to hypoxia, much less is known about HIF-3. The HIF-3␣ gene gives rise to multiple HIF-3␣ variants due to the utilization of different promoters, different transcription initiation sites, and alternative splicing. These HIF-3␣ variants are expressed in different tissues, at different developmental stages, and are differentially regulated by hypoxia and other factors. Recent studies suggest that different HIF-3␣ variants have different and even opposite functions. There is strong evidence that full-length HIF-3␣ protein functions as an oxygen-regulated transcription activator and that it activates a unique transcriptional program in response to hypoxia. Many HIF-3␣ target genes have been identified. While some short HIF-3␣ variants act as dominant-negative regulators of HIF-1/2␣ actions, other HIF-3␣ variants can inhibit HIF-1/2␣ actions by competing for the common HIF-␤. There are also a number of HIF-3␣ variants yet to be explored. Future studies of these naturally occurring HIF-3␣ variants will provide new and important insights into HIF biology and may lead to the development of new therapeutic strategies.hypoxia-inducible factor; alternative splicing; oxygen-dependent degradation; gene expression OXYGEN IS AN ESSENTIAL MOLECULE required for cellular respiration and efficient energy production. Hypoxia, a condition in which an organism or a cell is deprived of adequate oxygen (e.g., when oxygen demand exceeds oxygen supply), occurs in developing embryos and adult tissues and plays key roles in stem cell biology, development, and adult physiology. Hypoxia is also frequently associated with pathological states such as ischemia, arthritis, inflammation, and tumorigenesis. Hypoxia triggers complex adaptive responses and activates the expression of numerous genes. These hypoxia-responsive genes are involved in changes in erythropoiesis, angiogenesis, metabolic reprograming, cell-cycle regulation, and tumorigenesis (9,39,(43)(44)(45). The transcriptional response to hypoxia is coordinated by hypoxiainducible factors (HIFs). HIFs are heterodimers, consisting of an oxygen-labile HIF␣ subunit and a stable HIF-␤ subunit [also known as aryl hydrocarbon receptor nuclear translocator (ARNT)]. In human and other vertebrate species, there are three distinct HIF␣ genes. Much of our knowledge about HIF signaling is derived from studies on HIF-1␣ and HIF-2␣ (9, 39, 43-45). Both HIF-1␣ and HIF-2␣ contain a basic helix-loophelix (bHLH) domain, two Per-Arnt-Sim (PAS) domains, a PAS-associated COOH-terminal (PAC) domain; an oxygendependent degradation (ODD) domain; an NH 2 -terminal transactivation domain (N...

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Section: Biological Function(s) Of Hif-3␣ Variantssupporting

confidence: 81%

Section: Biological Function(s) Of Hif-3␣ Variantssupporting

confidence: 77%

Hypoxia-inducible factor 3 biology: complexities and emerging themes

Duan

2016

American Journal of Physiology-Cell Physiology

203

172

View full text Add to dashboard Cite

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“…HIF-1α can also induce a variety of apoptosis-related proteins, such as the pro-apoptosis proteins BNIP3 and Noxa [28,29]. IPAS is a negative regulator of HIF-1 and leads to mitochondrial depolarization and caspase 3 activation by binding to Bcl-2 family members Bcl-xL, Bcl-w, and Mcl-1, thereby promoting cell apoptosis [30]. These data confirm the effect of HIF-1 with regard to inhibiting cell apoptosis, which mainly occurs through the mitochondria/caspase pathway.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of miR-184 Enhances the Malignant Biological Behavior of Human Glioma Cell Line A172 by Targeting FIH-1

Yuan

Gao

Liu

et al. 2014

Cell Physiol Biochem

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Background: In recent years, miRNAs have been suggested to play key roles in the formation and development of human glioma. The aim of this study is to investigate the effect and mechanism of miR-184 expression on the malignant behavior of human glioma cells. Methods: The relative quantity of miR-184 was determined in human glioma cell lines, and the expression of hypoxia-inducible factor-1 alpha (HIF-1α) was explored using western blotting. The effects of miR-184 inhibition on cell viability and apoptosis were explored, and the miR-184 target gene was determined using a luciferase assay and western blotting. Flow cytometry and Hoechst staining were used to evaluate cell growth and apoptosis. Matrigel invasion and scratch assays were performed to measure the ability of cell invasion and migration. Results: miR-184 and HIF-1α protein levels were significantly upregulated in human glioma cells. Downregulation of miR-184 inhibited cell viability and increased the HEB cell apoptotic rate. Luciferase and western blot assays verified that FIH-1 was the target gene of miR-184 and negatively controlled the protein level of HIF-1α. Inhibition of HIF-1α by siRNA facilitated the apoptosis of HEB cells and suppressed A172 cell invasion and migration. Conclusion: miR-184 upregulation enhanced the malignant phenotype of human glioma cancer cells by reducing FIH-1 protein expression.

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“…Nuclear translocation of HIF-1α is in need of the participation of its innate PAS domain and C-terminal nuclear transport signal, but how these sequences interact with oxygen-sensitive signals in detail still needs further clarification. HIF-1 could be negatively regulated by inhibitory PAS domain protein (IPAS), of which the pro-apoptotic activity is by way of binding to pro-survival Bcl-2 family proteins (77). To date it has been confirmed that in aerobic conditions the conserved proline residue in HIF-1α can be hydroxylated so that it can be recognized by the E3 ubiquitin ligase complex containing the tumor suppressor gene product VHL protein and undergo further proteasomal degradation (78).…”

Section: Vegf-related Hif-1 Involved In Hematological Malignancymentioning

confidence: 99%