Transcriptional regulation by hypoxia inducible factors

Dengler, Veronica L.; Galbraith, Matthew D.; Espinosa, Joaquín M.

doi:10.3109/10409238.2013.838205

Cited by 640 publications

(579 citation statements)

References 177 publications

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“…24 Since tumor VN is also characterized by a loss of hypoxia (and a return to normoxia) within the TME, 24,25 we analyzed treated vs. control tumors for expression of the hypoxiaassociated biomarker HIF-2a. [25][26][27] We determined that tumors in mice vaccinated with lvDLK1 or (more so) lvDLK1 C lvDLK2 displayed significant reductions in HIF-2a transcript levels vs. control-untreated tumors (Fig. 3D), consistent with therapeutic VN in these treatment cohorts.…”

Section: Resultssupporting

confidence: 51%

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

et al. 2017

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When compared with vascular cells in normal tissues, pericytes and vascular endothelial cells (VEC) in tumor blood vessels exhibit altered morphology and epigenetic programming that leads to the expression of unique antigens that allow for differential recognition by CD8 C T cells. We have previously shown that the Notch antagonist delta-like homolog 1 (DLK1) is a tumor pericyte-associated antigen expressed in setting of melanoma and a range of carcinomas. In this report, we show that therapeutic vaccination against DLK1 in murine models results in slowed tumor growth, but also to the compensatory expression of the DLK1 homolog, DLK2, by tumor-associated pericytes. Vaccines targeting both DLK1 and DLK2 resulted in superior antitumor benefits in association with improved activation and recruitment of antigen-specific Type 1 CD8 C T cells, reduced presence of myeloid-derived suppressive cells, T regulatory cell and tumor vascular normalization. The antitumor efficacy of vaccines coordinately targeting DLK1 and DLK2 was further improved by inclusion of PD-L1 blockade, thus defining a combination immunotherapy theoretically suitable for the treatment of a broad range of solid (vascularized) cancers.

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Section: Resultssupporting

confidence: 51%

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

et al. 2017

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“…In addition to oxygen-dependent stabilization of HIF-1α, HIF-1 is also controlled by mechanisms not directly involving oxygen but implicating oncogenic signaling pathways, protein interactions and diverse modifications (Dengler et al, 2014). Direct phosphorylation by kinases such as GSK3, PLK3, CDK1 and ATM (Kietzmann et al, 2016) affect HIF-1α protein stability, whereas others, such as ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively; hereafter referred to as ERK) (Mylonis et al, 2008) and CK1δ (CSNK1D) (Kalousi et al, 2010), control its activity by affecting nuclear accumulation or heterodimerization with ARNT, respectively.…”

Section: Introductionmentioning

confidence: 99%

Mortalin-mediated and ERK-controlled targeting of HIF-1α to mitochondria confers resistance to apoptosis under hypoxia

Mylonis

Kourti

Samiotaki

et al. 2017

Journal of Cell Science

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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-1α by inhibiting its CRM1 (XPO1)-dependent nuclear export. Here, we demonstrate that phosphorylation by ERK also regulates the association of HIF-1α with a so-far-unknown interaction partner identified as mortalin (also known as GRP75 and HSPA9), which mediates non-genomic involvement of HIF-1α in apoptosis. Mortalin binds specifically to HIF-1α that lacks modification by ERK, and the HIF-1α-mortalin complex is localized outside the nucleus. Under hypoxia, mortalin mediates targeting of unmodified HIF-1α 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-ΔC, and protection from apoptosis when ERK is inactivated. Under normoxia, transcriptionally inactive forms of unmodified HIF-1α or its C-terminal domain alone are also targeted to mitochondria, stimulate production of VDAC1-ΔC and increase resistance to etoposide-or doxorubicin-induced apoptosis. These findings reveal an ERK-controlled, unconventional and anti-apoptotic function of HIF-1α that might serve as an early protective mechanism upon oxygen limitation and promote cancer cell resistance to chemotherapy.

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“…Phosphorylation of HIF1α and HIF2α subunits has been demonstrated to enhance transactivation of target genes by either disrupting interaction with VHL and thereby stabilizing HIFs, or by increasing the affinity of HIFs for transcriptional coactivators [13]. In this regard, it has been reported that casein kinase II phosphorylates both HIF1α and HIF2α at conserved theonine residues in their C-TADs and that the mutation of these residues diminished their activity [48,49].…”

Section: Genes Regulated By Hif Alpha Subunitsmentioning

confidence: 99%

“…Comparatively, the bHLH and PAS domains of HIF3α share only 74% and 52-58% identity with HIF1α and HIF2α, respectively, revealing a more divergent nature of this paralog [13].…”

Section: Protein Structure Of the Oxygen-labile Alpha Subunitsmentioning

confidence: 99%

“…Under conditions of normal oxygen tension, the alpha subunits are hydroxylated at key proline and asparagine residues, which inhibits their transactivation function and targets them for proteasomal degradation. Upon hypoxia, the HIF alpha subunits are stabilized and accumulate in the nucleus, where they dimerize with HIF1β, allowing them bind to DNA and stimulate the transcription of their target genes [13]. However, multiple oxygen-independent mechanisms can also lead to HIF stabilization: growth factors, deregulated oncogenes, and/ or tumor suppressor-mediated signaling results in stabilized HIF alpha subunits.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Role of Hypoxia-Inducible Factors in Cancer Resistance

Saint-Martin¹,

Castañeda-Patlán²,

Robles-Flores³

2017

J Cell Signal

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Diminished oxygen availability (hypoxia) is a hallmark of the tumor microenvironment. A major regulator of cellular adaptation to hypoxia is the hypoxia-inducible factor (HIF) family of transcription factors, which play key roles in many crucial aspects of cancer biology including angiogenesis, stem cell maintenance, metabolic reprogramming, resistance to apoptosis, autocrine growth factor signaling, the EMT program, invasion and metastasis.Resistance to chemotherapy/radiotherapy is the primary cause for treatment failure in clinical oncology. Hypoxia and accumulation of hypoxia-inducible factors (HIFs) in solid tumors have been associated with resistance to treatment and poor prognosis. HIFs causes autophagy establishment to promote survival of cancer cells, and is also associated with the promotion and maintenance of cancer stem cells, a minority subpopulation within the tumor responsible for tumor recurrence and resistance to chemotherapy.In this review, we provide a concise comparative description of the structure, regulation, transcribed genes and roles played by each HIFα subunit in coordinating the transcriptional responses to hypoxia and on the roles they play in the promotion of resistance to anti-cancer therapy.

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Transcriptional regulation by hypoxia inducible factors

Cited by 640 publications

References 177 publications

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

Mortalin-mediated and ERK-controlled targeting of HIF-1α to mitochondria confers resistance to apoptosis under hypoxia

The Role of Hypoxia-Inducible Factors in Cancer Resistance

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