Intracrine prostaglandin E2 signalling regulates hypoxia-inducible factor-1α expression through retinoic acid receptor-β

Fernández‐Martínez, Ana B.; Jiménez, María Isabel Arenas; Manzano, Victoria Moreno; Lucio-Cazaña, Javier

doi:10.1016/j.biocel.2012.08.015

Cited by 14 publications

(6 citation statements)

References 26 publications

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“…Unlike results that occur in several other cells types (Ji et al, 2010; Fernandez-Martinez et al, 2012a; Fernandez-Martinez et al, 2012b), however, we found no increase in HIFα subunit expression by PGE 2 , although we did observe potent synergy between PGE 2 and hypoxia on HIF activity. This might occur through a PGE 2 dependent increase in HIFα activation that can occur independently of HIFα synthesis, as we reported for C/EBPδ and Runx2 (McCarthy et al, 2000c; Ji, 2003), but to our knowledge HIFα activation has not been previously addressed in this context.…”

Section: Discussioncontrasting

confidence: 99%

Stratified control of IGF-I expression by hypoxia and stress hormones in osteoblasts

McCarthy

Yun

Madri

et al. 2014

Gene

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Bone cells respond to the integrated effects of local and systemic regulation. Here we show that hypoxia and the stress hormones PGE2 and glucocorticoid interact in complex ways in osteoblasts, converging on insulin like growth factor I (IGF-I) expression. Whereas hypoxia alone rapidly increased transcription factor HIF activity, it suppressed DNA synthesis, had no significant effects on protein synthesis or alkaline phosphatase activity, and drove discrete changes in a panel of osteoblast mRNAs. Notably, hypoxia increased expression of the acute phase response transcription factors C/EBPδ which can induce IGF-I in response to PGE2, but conversely prevented the stimulatory effect of PGE2 on IGF-I mRNA. However, unlike its effect on C/EBPδ, hypoxia suppressed expression of the obligate osteoblast transcription factor Runx2, which can activate an upstream response element in the IGF-I gene promoter. Hypoxic inhibition of IGF-I and Runx2 were enforced by glucocorticoid, and continued with prolonged exposure. Our studies thus reveal that IGF-I expression is stratified by two critical transcriptional elements in osteoblasts, which are resolved by the individual and combined effects of hypoxic stress and stress hormones. In so doing, hypoxia suppresses Runx2, limits the enhancing influence of PGE2, and interacts with glucocorticoid to reduce IGF-I expression by osteoblasts.

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Section: Discussioncontrasting

confidence: 99%

Stratified control of IGF-I expression by hypoxia and stress hormones in osteoblasts

McCarthy

Yun

Madri

et al. 2014

Gene

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“…It is possible that multiple PGE 2 receptors on normal or RasV12 cells regulate the process of apical extrusion in a concerted manner. Alternatively, not only extracellular PGE 2 but also intracellular PGE 2 might modulate signalling pathways that affect apical extrusion [42][43][44] . It has been reported in Drosophila that various proinflammatory pathways are activated in loser cells, leading to their elimination from tissues 36,[45][46][47][48][49] .…”

Section: Discussionmentioning

confidence: 99%

The COX-2/PGE2 pathway suppresses apical elimination of RasV12-transformed cells from epithelia

et al. 2020

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At the initial stage of carcinogenesis, when RasV12-transformed cells are surrounded by normal epithelial cells, RasV12 cells are apically extruded from epithelia through cell competition with the surrounding normal cells. In this study, we demonstrate that expression of cyclooxygenase (COX)−2 is upregulated in normal cells surrounding RasV12-transformed cells. Addition of COX inhibitor or COX-2-knockout promotes apical extrusion of RasV12 cells. Furthermore, production of Prostaglandin (PG) E 2 , a downstream prostanoid of COX-2, is elevated in normal cells surrounding RasV12 cells, and addition of PGE 2 suppresses apical extrusion of RasV12 cells. In a cell competition mouse model, expression of COX-2 is elevated in pancreatic epithelia harbouring RasV12-exressing cells, and the COX inhibitor ibuprofen promotes apical extrusion of RasV12 cells. Moreover, caerulein-induced chronic inflammation substantially suppresses apical elimination of RasV12 cells. These results indicate that intrinsically or extrinsically mediated inflammation can promote tumour initiation by diminishing cell competition between normal and transformed cells.

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“…However, the mechanisms whereby PGE 2 modulates HSPC CXCR4 and homing are unknown. In prostate cancer cells and renal tubular cells, 21,22 PGE 2 stabilizes HIF1a protein without affecting messenger RNA (mRNA), and inhibiting PGE 2 biosynthesis reduces HIF1a and HIF-responsive genes. 23 In HEK cells and in microglial cells, HIF1a upregulates CXCR4 by interacting with hypoxia response elements (HREs) within the CXCR4 promoter.…”

Section: Resultsmentioning

confidence: 99%

“…12 HIF1a dose-dependently regulates HSC activity, 9 and intracellular oxygenation status plays a role in HSC quiescence and expansion. 9,13,14 Given that HIF1a and hypoxia regulate CXCR4 transcription in some cancer cell lines [15][16][17][18][19][20] and PGE 2 can stabilize HIF1a in prostate cancer cells, [21][22][23] we hypothesized that PGE 2 may increase CXCR4 and HSC engraftment through effects on HIF1a. Herein, we demonstrate that PGE 2 stabilizes HIF1a protein and transcriptional activity, which is required for enhanced HSPC homing, and identify a pharmacologic target for ex vivo enhancement of HSC function.…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic increase in HIF1α enhances hematopoietic stem and progenitor homing and engraftment

Speth

Hoggatt

Singh

et al. 2014

Blood

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Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for a number of immunologic disorders. For effective transplant, HSCs must traffic from the peripheral blood to supportive bone marrow niches. We previously showed that HSC trafficking can be enhanced by ex vivo treatment of hematopoietic grafts with 16-16 dimethyl prostaglandin E 2 (dmPGE 2 ). While exploring regulatory molecules involved in dmPGE 2 enhancement, we found that transiently increasing the transcription factor hypoxiainducible factor 1-a (HIF1a) is required for dmPGE 2 -enhanced CXCR4 upregulation and enhanced migration and homing of stem and progenitor cells and that pharmacologic manipulation of HIF1a is also capable of enhancing homing and engraftment. We also now identify the specific hypoxia response element required for CXCR4 upregulation. These data define a precise mechanism through which ex vivo pulse treatment with dmPGE 2 enhances the function of hematopoietic stem and progenitor cells; these data also define a role for hypoxia and HIF1a in enhancement of hematopoietic transplantation. (Blood. 2014;123(2):203-207) Introduction Hematopoietic stem cell (HSC) transplantation is a curative treatment of immunologic malignancies, inherited metabolic diseases, and congenital immunodeficiencies, and is an attractive method for gene therapy. Transplantation success is partly dictated by the quality and number of donor cells transplanted, and is dependent on their ability to home to bone marrow (BM) niches, self-renew and differentiate. Some sources of HSCs display reduced engraftment efficiency because of inadequate number, and/or poor homing. Identifying strategies to enhance homing and expansion of HSCs can improve transplant efficiency, particularly when HSC number is limited. It is known that prostaglandin E 2 (PGE 2 ) can stimulate hematopoietic stem and progenitor cell (HSPC) proliferation.1,2 Recently, the long-acting PGE 2 analog 16-16 dimethyl PGE 2 (dmPGE 2 ) was identified in a zebrafish chemical screen as a regulator of hematopoiesis, and ex vivo exposure to dmPGE 2 was shown to increase engraftment in murine and nonhuman primate models. 3,4 This strategy has now progressed to a phase 1 clinical trial. 5 We previously demonstrated that part of the mechanisms of action for PGE 2 were the result of increases in homing, survival, and proliferation of murine and human HSCs.6 PGE 2 enhances HSC homing primarily by increasing CXCR4 expression on HSCs; however, the mechanism(s) whereby PGE 2 modulates CXCR4 and HSC homing has not been defined.HSCs have been reported to lie in hypoxic BM niches 7-10 that support stabilization of hypoxia-inducible factor 1 a (HIF1a) within HSCs. HSCs that reside in hypoxic niches have greater hematopoieticrepopulating ability, 11 although recent evidence suggests that HSCs may inherently maintain hypoxic status independently from their specific BM localization. 12 HIF1a dose-dependently regulates HSC activity, 9 and intracellular oxygenation status plays a role in HSC quiescence and expan...

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Intracrine prostaglandin E2 signalling regulates hypoxia-inducible factor-1α expression through retinoic acid receptor-β

Cited by 14 publications

References 26 publications

Stratified control of IGF-I expression by hypoxia and stress hormones in osteoblasts

Stratified control of IGF-I expression by hypoxia and stress hormones in osteoblasts

The COX-2/PGE2 pathway suppresses apical elimination of RasV12-transformed cells from epithelia

Pharmacologic increase in HIF1α enhances hematopoietic stem and progenitor homing and engraftment

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