Hypoxia-inducible factors: Crosstalk between inflammation and metabolism

Shay, Jessica E.S.; Simon, M. Celeste

doi:10.1016/j.semcdb.2012.04.004

Cited by 122 publications

(119 citation statements)

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“…In good agreement with the transcriptome data, the alleviation of GRmediated repression of HSF1 by 15d-PGJ 2 in GR SUMOylationcompetent cells resulted in robust expression of HSF1 target genes HSPA1A and HSPA1B. HIF1A belongs to the hypoxia-inducible factor family that plays a critical role in hypoxic stress (44,45). SUMOylation can also modulate the HIF1A action during hypoxia (46,47), and glucocorticoids are capable of suppressing HIF1A expression through the induction of glucocorticoid-induced leucine zipper (48).…”

Section: Discussionsupporting

confidence: 78%

Electrophilic Lipid Mediator 15-Deoxy-Δ^12,14-Prostaglandin J₂ Modifies Glucocorticoid Signaling via Receptor SUMOylation

Paakinaho

Kaikkonen

Levonen

2014

Molecular and Cellular Biology

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c Cortisol, the central stress hormone in humans, activates the glucocorticoid receptor (GR). Anti-inflammatory effects are the most important pharmaceutical effects mediated by the GR. Inasmuch as electrophilic cyclopentenone prostaglandin 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) has potent anti-inflammatory properties and activates the SUMOylation pathway, we have investigated the effect of 15d-PGJ 2 on glucocorticoid signaling and receptor SUMOylation. To this end, we studied isogenic HEK293 cells expressing either wild-type GR or SUMOylation-defective GR. Interestingly, 15d-PGJ 2 triggered SUMO-2 and -3 (SUMO-2/3) modification in the primary SUMOylation sites of the GR. Gene expression profiling and pathway analyses indicate that 15d-PGJ 2 inhibits GR signaling in a genome-wide fashion that is significantly dependent on the GR SUMOylation sites. Chromatin immunoprecipitation assays showed that the repressive effect of 15d-PGJ 2 on GR target gene expression occurs in parallel with the inhibition of receptor binding to the target gene chromatin. Furthermore, depletion of UBC9, the sole SUMO E2 conjugase, from HEK293 cells confirmed the involvement of active SUMOylation in the regulatory process. Taken together, our data indicate that GR SUMOylation modulates the glucocorticoid signaling during acute cell stress. Our data also suggest that GR SUMOylation modulates cross talk of the glucocorticoid signaling with other transcription factors that are responsive to cell stress.

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Section: Discussionsupporting

confidence: 78%

Electrophilic Lipid Mediator 15-Deoxy-Δ^12,14-Prostaglandin J₂ Modifies Glucocorticoid Signaling via Receptor SUMOylation

Paakinaho

Kaikkonen

Levonen

2014

Molecular and Cellular Biology

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“…Hypoxia is characterized by lack of O 2 , and hypoxic tissues are inadequately oxygenated (107). A physiologically hypoxic microenvironment has been observed in a variety of normal tissues, including retina, kidney medulla, skin epidermis, and hypoxic niches within the bone marrow (103).…”

Section: Hypoxia As An Integral Component Of the Tumor Microenvironmentmentioning

confidence: 99%

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Noman

Hasmim

Messai

et al. 2015

American Journal of Physiology-Cell Physiology

320

310

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-The tumor microenvironment is a complex system, playing an important role in tumor development and progression. Besides cellular stromal components, extracellular matrix fibers, cytokines, and other metabolic mediators are also involved. In this review we outline the potential role of hypoxia, a major feature of most solid tumors, within the tumor microenvironment and how it contributes to immune resistance and immune suppression/tolerance and can be detrimental to antitumor effector cell functions. We also outline how hypoxic stress influences immunosuppressive pathways involving macrophages, myeloid-derived suppressor cells, T regulatory cells, and immune checkpoints and how it may confer tumor resistance. Finally, we discuss how microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions.hypoxia; hypoxia-inducible factor; tumor microenvironment; myeloid cells; lymphoid cells; immune suppression; cancer stem cells; programmed death-ligand 1; epithelial-mesenchymal transition; circulating tumor cells; autophagy and antitumor immune response IT HAS BECOME INCREASINGLY apparent that malignant cells exist in a complex cellular and extracellular microenvironment that plays key roles in the initiation and maintenance of the malignant phenotype. Among the microenvironmental factors that play a dominant role in neoplasia, hypoxia is believed to be one of the most relevant in the neoplastic response of tumor cells. It is widely appreciated that the majority of malignancies create a hostile hypoxic microenvironment that can hamper cellmediated immunity and dampen the efficacy of the immune response. Poorly vascularized and hypoxic zones inside solid tumors contribute to immune tolerance of tumor cells by impeding the homing of immunocompetent cells into tumors and inhibiting their antitumor efficacy. Several regulatory mechanisms can occur concurrently within the hypoxic tumor microenvironment, resulting in multiple redundant levels of immune cell plasticity and suppression, tumor plasticity, and functional heterogeneity. Hypoxic stress clearly plays a crucial role in tumor promotion and immune escape by controlling angiogenesis and favoring immune suppression and tumor resistance. Like other therapeutic attempts, immunotherapy is heavily hampered by the morphologically aberrant tumor microvasculature, preventing migration of immune effector cells into established tumors. Many strategies are emerging for changing the immunosuppressive nature of the tumor to a microenvironment able to support antitumor immunity. The identification of ways to induce a permissive and less hostile tumor microenvironment to avoid tumor resistance and immune suppression is of major interest and pertinence. Hypoxia as an Integral Component of the Tumor MicroenvironmentAll life on Earth depends on O 2 , and all physiological and pathological processes of a living cell rely principally on O 2 (103). Hypoxia is characterized by lack of O 2 , and hypoxic tissues are inadequately oxygenated (107). A p...

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“…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).…”

mentioning

confidence: 99%

“…They dimerize with HIF-␤, translocate into the nucleus, recruit coactivators such as P300/CBP, and bind to hypoxia response elements (HRE: [A/G]CGTG) in the promoter regions of the target genes. The HIF-1/2␣ transactivation activity is further increased due to the reduced asparaginyl hydroxylation (9,39,(43)(44)(45). The resultant increases in the HIF-1/2 target genes lead to numerous adaptive changes.…”

mentioning

confidence: 99%

Hypoxia-inducible factor 3 biology: complexities and emerging themes

Duan

2016

American Journal of Physiology-Cell Physiology

197

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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Hypoxia-inducible factors: Crosstalk between inflammation and metabolism

Cited by 122 publications

References 59 publications

Electrophilic Lipid Mediator 15-Deoxy-Δ^12,14-Prostaglandin J₂ Modifies Glucocorticoid Signaling via Receptor SUMOylation

Electrophilic Lipid Mediator 15-Deoxy-Δ^12,14-Prostaglandin J₂ Modifies Glucocorticoid Signaling via Receptor SUMOylation

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Hypoxia-inducible factor 3 biology: complexities and emerging themes

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Hypoxia-inducible factors: Crosstalk between inflammation and metabolism

Cited by 122 publications

References 59 publications

Electrophilic Lipid Mediator 15-Deoxy-Δ12,14-Prostaglandin J2 Modifies Glucocorticoid Signaling via Receptor SUMOylation

Electrophilic Lipid Mediator 15-Deoxy-Δ12,14-Prostaglandin J2 Modifies Glucocorticoid Signaling via Receptor SUMOylation

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Hypoxia-inducible factor 3 biology: complexities and emerging themes

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Electrophilic Lipid Mediator 15-Deoxy-Δ^12,14-Prostaglandin J₂ Modifies Glucocorticoid Signaling via Receptor SUMOylation

Electrophilic Lipid Mediator 15-Deoxy-Δ^12,14-Prostaglandin J₂ Modifies Glucocorticoid Signaling via Receptor SUMOylation