Normoxic stabilization of hypoxia-inducible factor-1α by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1
Hypoxia-inducible factor (HIF) is a transcription factor with major roles in many cellular and systemic responses to hypoxia. Activation of HIF pathways under hypoxia is mediated by suppression of the Fe²⁺ - and O₂-dependent HIF hydroxylase enzymes that normally inactive HIFα subunits. Mechanisms un...
| Main Authors: | , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Association for Cancer Research
2006
|
| Subjects: |
| _version_ | 1797082257430675456 |
|---|---|
| author | Knowles, H Mole, D Ratcliffe, P Harris, A |
| author_facet | Knowles, H Mole, D Ratcliffe, P Harris, A |
| author_sort | Knowles, H |
| collection | OXFORD |
| description | Hypoxia-inducible factor (HIF) is a transcription factor with major roles in many cellular and systemic responses to hypoxia. Activation of HIF pathways under hypoxia is mediated by suppression of the Fe²⁺ - and O₂-dependent HIF hydroxylase enzymes that normally inactive HIFα subunits. Mechanisms underlying induction of HIF in normoxic conditions are less clearly understood. In human cancers, infiltrating macrophages show up-regulation of HIF and it has recently been shown that normoxic expression of HIF-1α is essential for macrophage function. Here, we report studies of HIF-α induction following phorbol-12-myristate 13-acetate (PMA)-induced differntiation of monocytic U937 and THP1 cells. HIF-1α was markedly up-regulated under normoxia in this setting and this involved failure of HIF-1α prolyl hydroxylation despite the presence of O₂. Fluorescence measurements showed that differentiation was associated with marked reduction of the labile iron pool. Both the reduction in labile iron pool and the up-regulation of HIF-1α were suppressed by RNA interference-mediated down-regulation of the iron transporter natural resistance-associated macrophage protein 1. Up-regulation of HIF-1α following PMA-induced differentiation was also abolished by addition of Fe²⁺ or ascorbate. These results indicate that physiologic changes in macrophage iron metabolism have an important effect on HIF hydroxylase pathways and suggest means by which the system could be manipulated for therapeutic benefit. |
| first_indexed | 2024-03-07T01:25:33Z |
| format | Journal article |
| id | oxford-uuid:91dc7093-954a-4ef9-95ec-636edd4369f9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:25:33Z |
| publishDate | 2006 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | oxford-uuid:91dc7093-954a-4ef9-95ec-636edd4369f92022-03-26T23:21:30ZNormoxic stabilization of hypoxia-inducible factor-1α by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:91dc7093-954a-4ef9-95ec-636edd4369f9Medical sciencesOncologyPhysiologyEnglishOxford University Research Archive - ValetAmerican Association for Cancer Research2006Knowles, HMole, DRatcliffe, PHarris, AHypoxia-inducible factor (HIF) is a transcription factor with major roles in many cellular and systemic responses to hypoxia. Activation of HIF pathways under hypoxia is mediated by suppression of the Fe²⁺ - and O₂-dependent HIF hydroxylase enzymes that normally inactive HIFα subunits. Mechanisms underlying induction of HIF in normoxic conditions are less clearly understood. In human cancers, infiltrating macrophages show up-regulation of HIF and it has recently been shown that normoxic expression of HIF-1α is essential for macrophage function. Here, we report studies of HIF-α induction following phorbol-12-myristate 13-acetate (PMA)-induced differntiation of monocytic U937 and THP1 cells. HIF-1α was markedly up-regulated under normoxia in this setting and this involved failure of HIF-1α prolyl hydroxylation despite the presence of O₂. Fluorescence measurements showed that differentiation was associated with marked reduction of the labile iron pool. Both the reduction in labile iron pool and the up-regulation of HIF-1α were suppressed by RNA interference-mediated down-regulation of the iron transporter natural resistance-associated macrophage protein 1. Up-regulation of HIF-1α following PMA-induced differentiation was also abolished by addition of Fe²⁺ or ascorbate. These results indicate that physiologic changes in macrophage iron metabolism have an important effect on HIF hydroxylase pathways and suggest means by which the system could be manipulated for therapeutic benefit. |
| spellingShingle | Medical sciences Oncology Physiology Knowles, H Mole, D Ratcliffe, P Harris, A Normoxic stabilization of hypoxia-inducible factor-1α by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1 |
| title | Normoxic stabilization of hypoxia-inducible factor-1α by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1 |
| title_full | Normoxic stabilization of hypoxia-inducible factor-1α by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1 |
| title_fullStr | Normoxic stabilization of hypoxia-inducible factor-1α by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1 |
| title_full_unstemmed | Normoxic stabilization of hypoxia-inducible factor-1α by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1 |
| title_short | Normoxic stabilization of hypoxia-inducible factor-1α by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1 |
| title_sort | normoxic stabilization of hypoxia inducible factor 1α by modulation of the labile iron pool in differentiating u937 macrophages effect of natural resistance associated macrophage protein 1 |
| topic | Medical sciences Oncology Physiology |
| work_keys_str_mv | AT knowlesh normoxicstabilizationofhypoxiainduciblefactor1abymodulationofthelabileironpoolindifferentiatingu937macrophageseffectofnaturalresistanceassociatedmacrophageprotein1 AT moled normoxicstabilizationofhypoxiainduciblefactor1abymodulationofthelabileironpoolindifferentiatingu937macrophageseffectofnaturalresistanceassociatedmacrophageprotein1 AT ratcliffep normoxicstabilizationofhypoxiainduciblefactor1abymodulationofthelabileironpoolindifferentiatingu937macrophageseffectofnaturalresistanceassociatedmacrophageprotein1 AT harrisa normoxicstabilizationofhypoxiainduciblefactor1abymodulationofthelabileironpoolindifferentiatingu937macrophageseffectofnaturalresistanceassociatedmacrophageprotein1 |