Journal
JOURNAL OF CELL SCIENCE
Volume 130, Issue 2, Pages 466-479Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.195339
Keywords
Hypoxia; Apoptosis; HIF-1; Mortalin; Mitochondria; ERK
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Funding
- ARISTEIA II' Action of the 'Operational Program Education and Lifelong Learning - European Social Fund (ESF) [ARISTEIA II HYPOXYTARGET 3129]
- Greek National Resources (General Secretariat for Research and Technology)
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Hypoxia inducible factor-1 (HIF-1) is the main transcriptional activator of the cellular response to hypoxia and an important target of anticancer therapy. Phosphorylation by ERK1 and/or ERK2 (MAPK3 and MAPK1, respectively; hereafter ERK) stimulates the transcriptional activity of HIF-1 alpha by inhibiting its CRM1 (XPO1)-dependent nuclear export. Here, we demonstrate that phosphorylation by ERK also regulates the association of HIF-1 alpha with a so-far-unknown interaction partner identified as mortalin (also known as GRP75 and HSPA9), which mediates non-genomic involvement of HIF- 1 alpha in apoptosis. Mortalin binds specifically to HIF- 1a that lacks modification by ERK, and the HIF-1 alpha-mortalin complex is localized outside the nucleus. Under hypoxia, mortalin mediates targeting of unmodified HIF-1 alpha to the outer mitochondrial membrane, as well as association with VDAC1 and hexokinase II, which promotes production of a C-terminally truncated active form of VDAC1, denoted VDAC1-Delta C, and protection from apoptosis when ERK is inactivated. Under normoxia, transcriptionally inactive forms of unmodified HIF-1 alpha or its C-terminal domain alone are also targeted to mitochondria, stimulate production of VDAC1-Delta C and increase resistance to etoposide-or doxorubicin-induced apoptosis. These findings reveal an ERK-controlled, unconventional and anti-apoptotic function of HIF-1 alpha that might serve as an early protective mechanism upon oxygen limitation and promote cancer cell resistance to chemotherapy.
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