Hypoxia-inducible Factor-1 Deficiency Results in Dysregulated Erythropoiesis Signaling and Iron Homeostasis in Mouse Development

Yoon, Donghoon; Pastore, Yves D.; Divoký, Vladimír; Liu, Enli; Mlodnicka, Agnieszka E.; Rainey, Karin; Ponka, P; Semenza, Gregg L.; Schumacher, Armin; Prchal, Josef T.

doi:10.1074/jbc.m602329200

Cited by 210 publications

(177 citation statements)

References 47 publications

Supporting

Mentioning

159

Contrasting

Unclassified

Order By: Relevance

“…HIF-1 also down-regulates some target genes such as α-fetoprotein (13) and hepcidin (14). HIF-1-deficient mice show abnormal iron regulation (15). Down-regulation of DNM2 increases HIF-1α and HIF-2α stabilization.…”

Section: Discussionmentioning

confidence: 99%

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

Joshi¹,

Subramanian²,

Schnettler³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hypoxia-driven changes in the tumor microenvironment facilitate cancer metastasis. In the present study, we investigated the regulatory cross talk between endocytic pathway, hypoxia, and tumor metastasis. Dynamin 2 (DNM2), a GTPase, is a critical mediator of endocytosis. Hypoxia decreased the levels of DNM2. DNM2 promoter has multiple hypoxia-inducible factor (HIF)-binding sites and genetic deletion of them relieved hypoxia-induced transcriptional suppression. Interestingly, DNM2 reciprocally regulated HIF. Inhibition of DNM2 GTPase activity and dominantnegative mutant of DNM2 showed a functional role for DNM2 in regulating HIF. Furthermore, the opposite strand of DNM2 gene encodes miR-199a, which is similarly reduced in cancer cells under hypoxia. miR-199a targets the 3′-UTR of HIF-1α and HIF-2α. Decreased miR-199a expression in hypoxia increased HIF levels. Exogenous expression of miR-199a decreased HIF, cell migration, and metastasis of ovarian cancer cells. miR-199a-mediated changes in HIF levels affected expression of the matrix-remodeling enzyme, lysyloxidase (LOX). LOX levels negatively correlated with progression-free survival in ovarian cancer patients. These results demonstrate a regulatory relationship between DNM2, miR199a, and HIF, with implications in cancer metastasis.microRNA | iron regulation E pithelial ovarian cancer (EOC) is the leading cause of death among the gynecological malignancies (1). Ascites development and peritoneal metastasis are unique features of ovarian cancer progression. Gas analyses of ovarian cancer ascites show about 2.5% dissolved oxygen content, whereas the blood oxygen content ranges between 15% and 23% (2). Hypoxic areas are common in tumor microenvironment as increased metabolic demands of rapidly proliferating cells outpace oxygen availability. Sustained exposure to hypoxia spurs cells to reorganize cellular processes, and energy-consuming functions, such as endocytosis, are suppressed (3, 4). Hypoxia-inducible factor-1α and hypoxia-inducible factor-2α (HIF-1α/HIF-2α) are principal coordinators of these responses. HIF-1α/HIF-2α are stabilized in hypoxia and associate with hypoxia-inducible factor-1β (HIF-1β) to form heterodimeric transcription factors and induce the expression of target genes (5, 6). HIF-1-mediated expression of lysyloxidase (LOX) cross-links collagens and induces cell migration (7). Epithelial ovarian cancer cells (EOCCs) that have adapted to hypoxia by activating HIF-1 disseminate from primary ovarian tumors and exfoliate into the peritoneal cavity. HIF-1 significantly enhances gene signatures associated with tissue remodeling, the morbidity and mortality associated with EOC (8, 9).Regulation of HIF-1 is a key step in the hypoxic response with profound implications for EOC metastasis. Under normoxia, HIF-1α is hydroxylated within its oxygen-dependent degradation domain (ODDD) by prolylhydroxylases (PHDs). This reaction is an oxygen-, iron-, 2-oxoglutarate and ascorbate-dependent process. Hydroxylated HIF-1α is recognized and bound by a complex that...

show abstract

Section: Discussionmentioning

confidence: 99%

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

Joshi¹,

Subramanian²,

Schnettler³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…10,12,26,31 Both EPO and the EpoR are regulated through a hypoxia-based mechanism involving hypoxia-inducible factor (HIF) as well as via additional mechanisms involving hypoglycemia, intracellular calcium level and cytokines. [32][33][34] Regulation of EPO through an HIF-1a-independent mechanism also has been recently reported. 35 In our study, we determined that treatment with EPO reduced the number of activated lung endothelial cells 6-fold in animals treated with bleomycin, as evidenced by changes in morphology.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin ameliorates chemotherapy‐induced fibrosis of the lungs in a preclinical murine model

Sigounas

Salleng

Mehlhop

et al. 2008

Intl Journal of Cancer

View full text Add to dashboard Cite

Organ toxicity induced by chemotherapeutic drugs is a serious obstacle in the effective treatment of patients suffering from cancer and autoimmune disease. A strong association exists between pulmonary toxicity, particularly fibrosis, and chemotherapeutic drugs. Attempts have been made to identify compounds capable of suppressing fibrosis. In addition to its erythropoietic activity, erythropoietin (EPO) has been shown to have effects on nonhemopoietic cells. Therefore, we postulated that EPO may exert beneficial effects on lung tissue during chemotherapy. To test our hypothesis, we investigated pulmonary changes caused by bleomycin, a fibrosis‐inducing agent, in animals treated with the drug alone and in combination with EPO. Fibrosis, cellular alterations and structural changes were assayed by blind analysis of the lung sections. A 6‐fold decrease in the number of prominent endothelial cells—suspected to be indicative of cellular activation and inflammatory response—was observed in lung sections derived from mice treated with bleomycin and EPO compared to animals injected with bleomycin alone (p < 0.008). Additionally, there was twice the number of ICAM1‐positive endothelial cells in animals treated with bleomycin alone compared with the number in the bleomycin and EPO‐treated group (p < 0.05). Alveolar mononuclear phagocytic hyperplasia was reduced by as much as 100% in animals treated with bleomycin and EPO compared to animals treated with bleomycin alone (p < 0.03). Finally, a 5‐fold decrease in interstitial fibrosis was observed in lung sections obtained from animals treated with bleomycin and EPO (p < 0.02). We conclude that EPO can ameliorate drug‐induced fibrosis and endothelial damage caused by chemotherapeutic agents. © 2008 Wiley‐Liss, Inc.

show abstract

“…HIF-1 (2,20) and HIF-2 (3,(21)(22)(23)(24) contribute to regulation of Epo gene expression to a differing extent in cells and in mice. Candidate acetyltransferases that modulate HIF signaling include p300/CBP (25) and PCAF/GCN5 (26) family members.…”

Section: Discussionmentioning

confidence: 99%

“…HIF-1 and HIF-2 regulate unique and shared target genes whose products control adaptive cellular and physiological processes. For example, erythropoiesis is regulated at distinct developmental stages by HIF-1 and HIF-2 through control of erythropoietin (Epo), one of the most highly induced hypoxia-responsive target genes in mammals (2,3).…”

mentioning

confidence: 99%

The Acetylase/Deacetylase Couple CREB-binding Protein/Sirtuin 1 Controls Hypoxia-inducible Factor 2 Signaling

Chen

Hogg

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Hypoxia-inducible Factor-1 Deficiency Results in Dysregulated Erythropoiesis Signaling and Iron Homeostasis in Mouse Development

Cited by 210 publications

References 47 publications

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

Erythropoietin ameliorates chemotherapy‐induced fibrosis of the lungs in a preclinical murine model

The Acetylase/Deacetylase Couple CREB-binding Protein/Sirtuin 1 Controls Hypoxia-inducible Factor 2 Signaling

Contact Info

Product

Resources

About