The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability

Abstract The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two ma...
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Autor*in:	Maciej Jaśkiewicz [verfasserIn] Adrianna Moszyńska [verfasserIn] Jarosław Króliczewski [verfasserIn] Aleksandra Cabaj [verfasserIn] Sylwia Bartoszewska [verfasserIn] Agata Charzyńska [verfasserIn] Magda Gebert [verfasserIn] Michał Dąbrowski [verfasserIn] James F. Collawn [verfasserIn] Rafal Bartoszewski [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	Hypoxia Human endothelial cells HIF1A EPAS1 HIF-1α HIF-2α

Übergeordnetes Werk:	In: Cellular & Molecular Biology Letters - BMC, 2018, 27(2022), 1, Seite 19
Übergeordnetes Werk:	volume:27 ; year:2022 ; number:1 ; pages:19

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.1186/s11658-022-00408-7

Katalog-ID:	DOAJ083462910

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520			\|a Abstract The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha–beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 h of hypoxia in primary endothelial cells and then is dramatically reduced by 8 h. In contrast, HIF-2 is maximal at 8 h and remains elevated up to 24 h. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α (HIF1A) compared to HIF-2α (EPAS1) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia.
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allfields	10.1186/s11658-022-00408-7 doi (DE-627)DOAJ083462910 (DE-599)DOAJ75c92cbadd1f4810a08902d147f250fb DE-627 ger DE-627 rakwb eng QH573-671 Maciej Jaśkiewicz verfasserin aut The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha–beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 h of hypoxia in primary endothelial cells and then is dramatically reduced by 8 h. In contrast, HIF-2 is maximal at 8 h and remains elevated up to 24 h. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α (HIF1A) compared to HIF-2α (EPAS1) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia. Hypoxia Human endothelial cells HIF1A EPAS1 HIF-1α HIF-2α Cytology Adrianna Moszyńska verfasserin aut Jarosław Króliczewski verfasserin aut Aleksandra Cabaj verfasserin aut Sylwia Bartoszewska verfasserin aut Agata Charzyńska verfasserin aut Magda Gebert verfasserin aut Michał Dąbrowski verfasserin aut James F. Collawn verfasserin aut Rafal Bartoszewski verfasserin aut In Cellular & Molecular Biology Letters BMC, 2018 27(2022), 1, Seite 19 (DE-627)363772340 (DE-600)2108724-6 16891392 nnns volume:27 year:2022 number:1 pages:19 https://doi.org/10.1186/s11658-022-00408-7 kostenfrei https://doaj.org/article/75c92cbadd1f4810a08902d147f250fb kostenfrei https://doi.org/10.1186/s11658-022-00408-7 kostenfrei https://doaj.org/toc/1425-8153 Journal toc kostenfrei https://doaj.org/toc/1689-1392 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2014 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 1 19
spelling	10.1186/s11658-022-00408-7 doi (DE-627)DOAJ083462910 (DE-599)DOAJ75c92cbadd1f4810a08902d147f250fb DE-627 ger DE-627 rakwb eng QH573-671 Maciej Jaśkiewicz verfasserin aut The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha–beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 h of hypoxia in primary endothelial cells and then is dramatically reduced by 8 h. In contrast, HIF-2 is maximal at 8 h and remains elevated up to 24 h. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α (HIF1A) compared to HIF-2α (EPAS1) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia. Hypoxia Human endothelial cells HIF1A EPAS1 HIF-1α HIF-2α Cytology Adrianna Moszyńska verfasserin aut Jarosław Króliczewski verfasserin aut Aleksandra Cabaj verfasserin aut Sylwia Bartoszewska verfasserin aut Agata Charzyńska verfasserin aut Magda Gebert verfasserin aut Michał Dąbrowski verfasserin aut James F. Collawn verfasserin aut Rafal Bartoszewski verfasserin aut In Cellular & Molecular Biology Letters BMC, 2018 27(2022), 1, Seite 19 (DE-627)363772340 (DE-600)2108724-6 16891392 nnns volume:27 year:2022 number:1 pages:19 https://doi.org/10.1186/s11658-022-00408-7 kostenfrei https://doaj.org/article/75c92cbadd1f4810a08902d147f250fb kostenfrei https://doi.org/10.1186/s11658-022-00408-7 kostenfrei https://doaj.org/toc/1425-8153 Journal toc kostenfrei https://doaj.org/toc/1689-1392 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2014 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 1 19
allfields_unstemmed	10.1186/s11658-022-00408-7 doi (DE-627)DOAJ083462910 (DE-599)DOAJ75c92cbadd1f4810a08902d147f250fb DE-627 ger DE-627 rakwb eng QH573-671 Maciej Jaśkiewicz verfasserin aut The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha–beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 h of hypoxia in primary endothelial cells and then is dramatically reduced by 8 h. In contrast, HIF-2 is maximal at 8 h and remains elevated up to 24 h. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α (HIF1A) compared to HIF-2α (EPAS1) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia. Hypoxia Human endothelial cells HIF1A EPAS1 HIF-1α HIF-2α Cytology Adrianna Moszyńska verfasserin aut Jarosław Króliczewski verfasserin aut Aleksandra Cabaj verfasserin aut Sylwia Bartoszewska verfasserin aut Agata Charzyńska verfasserin aut Magda Gebert verfasserin aut Michał Dąbrowski verfasserin aut James F. Collawn verfasserin aut Rafal Bartoszewski verfasserin aut In Cellular & Molecular Biology Letters BMC, 2018 27(2022), 1, Seite 19 (DE-627)363772340 (DE-600)2108724-6 16891392 nnns volume:27 year:2022 number:1 pages:19 https://doi.org/10.1186/s11658-022-00408-7 kostenfrei https://doaj.org/article/75c92cbadd1f4810a08902d147f250fb kostenfrei https://doi.org/10.1186/s11658-022-00408-7 kostenfrei https://doaj.org/toc/1425-8153 Journal toc kostenfrei https://doaj.org/toc/1689-1392 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2014 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 1 19
allfieldsGer	10.1186/s11658-022-00408-7 doi (DE-627)DOAJ083462910 (DE-599)DOAJ75c92cbadd1f4810a08902d147f250fb DE-627 ger DE-627 rakwb eng QH573-671 Maciej Jaśkiewicz verfasserin aut The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha–beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 h of hypoxia in primary endothelial cells and then is dramatically reduced by 8 h. In contrast, HIF-2 is maximal at 8 h and remains elevated up to 24 h. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α (HIF1A) compared to HIF-2α (EPAS1) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia. Hypoxia Human endothelial cells HIF1A EPAS1 HIF-1α HIF-2α Cytology Adrianna Moszyńska verfasserin aut Jarosław Króliczewski verfasserin aut Aleksandra Cabaj verfasserin aut Sylwia Bartoszewska verfasserin aut Agata Charzyńska verfasserin aut Magda Gebert verfasserin aut Michał Dąbrowski verfasserin aut James F. Collawn verfasserin aut Rafal Bartoszewski verfasserin aut In Cellular & Molecular Biology Letters BMC, 2018 27(2022), 1, Seite 19 (DE-627)363772340 (DE-600)2108724-6 16891392 nnns volume:27 year:2022 number:1 pages:19 https://doi.org/10.1186/s11658-022-00408-7 kostenfrei https://doaj.org/article/75c92cbadd1f4810a08902d147f250fb kostenfrei https://doi.org/10.1186/s11658-022-00408-7 kostenfrei https://doaj.org/toc/1425-8153 Journal toc kostenfrei https://doaj.org/toc/1689-1392 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2014 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 1 19
allfieldsSound	10.1186/s11658-022-00408-7 doi (DE-627)DOAJ083462910 (DE-599)DOAJ75c92cbadd1f4810a08902d147f250fb DE-627 ger DE-627 rakwb eng QH573-671 Maciej Jaśkiewicz verfasserin aut The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha–beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 h of hypoxia in primary endothelial cells and then is dramatically reduced by 8 h. In contrast, HIF-2 is maximal at 8 h and remains elevated up to 24 h. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α (HIF1A) compared to HIF-2α (EPAS1) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia. Hypoxia Human endothelial cells HIF1A EPAS1 HIF-1α HIF-2α Cytology Adrianna Moszyńska verfasserin aut Jarosław Króliczewski verfasserin aut Aleksandra Cabaj verfasserin aut Sylwia Bartoszewska verfasserin aut Agata Charzyńska verfasserin aut Magda Gebert verfasserin aut Michał Dąbrowski verfasserin aut James F. Collawn verfasserin aut Rafal Bartoszewski verfasserin aut In Cellular & Molecular Biology Letters BMC, 2018 27(2022), 1, Seite 19 (DE-627)363772340 (DE-600)2108724-6 16891392 nnns volume:27 year:2022 number:1 pages:19 https://doi.org/10.1186/s11658-022-00408-7 kostenfrei https://doaj.org/article/75c92cbadd1f4810a08902d147f250fb kostenfrei https://doi.org/10.1186/s11658-022-00408-7 kostenfrei https://doaj.org/toc/1425-8153 Journal toc kostenfrei https://doaj.org/toc/1689-1392 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2014 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 1 19
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source	In Cellular & Molecular Biology Letters 27(2022), 1, Seite 19 volume:27 year:2022 number:1 pages:19
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authorswithroles_txt_mv	Maciej Jaśkiewicz @@aut@@ Adrianna Moszyńska @@aut@@ Jarosław Króliczewski @@aut@@ Aleksandra Cabaj @@aut@@ Sylwia Bartoszewska @@aut@@ Agata Charzyńska @@aut@@ Magda Gebert @@aut@@ Michał Dąbrowski @@aut@@ James F. Collawn @@aut@@ Rafal Bartoszewski @@aut@@
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topic_title	QH573-671 The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability Hypoxia Human endothelial cells HIF1A EPAS1 HIF-1α HIF-2α
topic	misc QH573-671 misc Hypoxia misc Human endothelial cells misc HIF1A misc EPAS1 misc HIF-1α misc HIF-2α misc Cytology
topic_unstemmed	misc QH573-671 misc Hypoxia misc Human endothelial cells misc HIF1A misc EPAS1 misc HIF-1α misc HIF-2α misc Cytology
topic_browse	misc QH573-671 misc Hypoxia misc Human endothelial cells misc HIF1A misc EPAS1 misc HIF-1α misc HIF-2α misc Cytology
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title	The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability
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title_full	The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability
author_sort	Maciej Jaśkiewicz
journal	Cellular & Molecular Biology Letters
journalStr	Cellular & Molecular Biology Letters
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author_browse	Maciej Jaśkiewicz Adrianna Moszyńska Jarosław Króliczewski Aleksandra Cabaj Sylwia Bartoszewska Agata Charzyńska Magda Gebert Michał Dąbrowski James F. Collawn Rafal Bartoszewski
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author-letter	Maciej Jaśkiewicz
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title_sort	transition from hif-1 to hif-2 during prolonged hypoxia results from reactivation of phds and hif1a mrna instability
callnumber	QH573-671
title_auth	The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability
abstract	Abstract The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha–beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 h of hypoxia in primary endothelial cells and then is dramatically reduced by 8 h. In contrast, HIF-2 is maximal at 8 h and remains elevated up to 24 h. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α (HIF1A) compared to HIF-2α (EPAS1) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia.
abstractGer	Abstract The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha–beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 h of hypoxia in primary endothelial cells and then is dramatically reduced by 8 h. In contrast, HIF-2 is maximal at 8 h and remains elevated up to 24 h. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α (HIF1A) compared to HIF-2α (EPAS1) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia.
abstract_unstemmed	Abstract The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha–beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 h of hypoxia in primary endothelial cells and then is dramatically reduced by 8 h. In contrast, HIF-2 is maximal at 8 h and remains elevated up to 24 h. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α (HIF1A) compared to HIF-2α (EPAS1) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia.
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title_short	The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability
url	https://doi.org/10.1186/s11658-022-00408-7 https://doaj.org/article/75c92cbadd1f4810a08902d147f250fb https://doaj.org/toc/1425-8153 https://doaj.org/toc/1689-1392
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author2	Adrianna Moszyńska Jarosław Króliczewski Aleksandra Cabaj Sylwia Bartoszewska Agata Charzyńska Magda Gebert Michał Dąbrowski James F. Collawn Rafal Bartoszewski
author2Str	Adrianna Moszyńska Jarosław Króliczewski Aleksandra Cabaj Sylwia Bartoszewska Agata Charzyńska Magda Gebert Michał Dąbrowski James F. Collawn Rafal Bartoszewski
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up_date	2024-07-03T17:36:58.250Z
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