FoxO Proteins Mediate Hypoxic Induction of Connective Tissue Growth Factor in Endothelial Cells

Samarin, Jana; Wessel, Julia; Cicha, Iwona; Kroening, Sven; Warnecke, Christina; Goppelt‐Struebe, Margarete

doi:10.1074/jbc.m109.049650

Cited by 35 publications

(28 citation statements)

References 43 publications

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“…The FOXO3 glutamine-synthetase-dependent autophagy occurs primarily in the perivenous zone [84] in which FOXO3 appeared to be primarily expressed and active. This feature goes nicely along with findings showing that FoxO3a transcription can be upregulated by HIF-1α in MEFs and NIH3T3 fibroblasts [85] and by the PHD inhibitor dimethyloxalyl glycine in a mouse glomerular microvascular endothelial cell line [86]. Moreover, prolylhydroxylation of FOXO3 by PHD1 ( egln2 ) destabilized it by inhibiting its interaction with one of the ubiquitin-specific protease family members (USP9x) [87].…”

Section: Hif Phds Redox and Zonationsupporting

confidence: 59%

Metabolic zonation of the liver: The oxygen gradient revisited

2017

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The liver has a multitude of functions which are necessary to maintain whole body homeostasis. This requires that various metabolic pathways can run in parallel in the most efficient manner and that futile cycles are kept to a minimum. To a large extent this is achieved due to a functional specialization of the liver parenchyma known as metabolic zonation which is often lost in liver diseases. Although this phenomenon is known for about 40 years, the underlying regulatory pathways are not yet fully elucidated. The physiologically occurring oxygen gradient was considered to be crucial for the appearance of zonation; however, a number of reports during the last decade indicating that β-catenin signaling, and the hedgehog (Hh) pathway contribute to metabolic zonation may have shifted this view. In the current review we connect these new observations with the concept that the oxygen gradient within the liver acinus is a regulator of zonation. This is underlined by a number of facts showing that the β-catenin and the Hh pathway can be modulated by the hypoxia signaling system and the hypoxia-inducible transcription factors (HIFs). Altogether, we provide a view by which the dynamic interplay between all these pathways can drive liver zonation and thus contribute to its physiological function.

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Section: Hif Phds Redox and Zonationsupporting

confidence: 59%

Metabolic zonation of the liver: The oxygen gradient revisited

2017

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“…More recently, FOXO proteins have been identified as key transcriptional mediators of HIF-induced CTGF expression in endothelial cells. 29 Further elucidation of the mechanisms by which HIF signaling increases CTGF expression may reveal additional opportunities for therapeutic intervention in the treatment of melanoma.…”

Section: Discussionmentioning

confidence: 99%

CTGF is a therapeutic target for metastatic melanoma

Cheng

et al. 2013

Oncogene

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Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression and is strongly induced by hypoxia through HIF-1 and HIF-2-dependent mechanisms. Genetic inhibition of CTGF in human melanoma cells is sufficient to significantly reduce orthotopic tumor growth, as well as metastatic tumor growth in the lung of severe combined immunodeficient (SCID) mice. Mechanistically, inhibition of CTGF decreased invasion and migration associated with reduced matrix metalloproteinase-9 expression. Most importantly, the anti-CTGF antibody, FG-3019, had a profound inhibitory effect on the progression of established metastatic melanoma. These results offer the first preclinical validation of anti-CTGF therapy for the treatment of advanced melanoma and underscore the importance of tumor hypoxia in melanoma progression.

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“…FoxO1 belongs to the fork-head family of transcriptional regulators and can be activated by reactive oxygen species [23,24]. Emerging evidence indicates that FoxO1 plays a critical role in regulating cellular functions under oxidative stress and acts downstream of p38 MAPK to mediate cell damage [25,26].…”

Section: Discussionmentioning

confidence: 99%

Tetramethylpyrazine Prevents Contrast-Induced Nephropathy by Inhibiting p38 MAPK and FoxO1 Signaling Pathways

Gong

Wang²,

Tang³

et al. 2013

Am J Nephrol

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Background: Apoptosis is recognized as an important mechanism in contrast-induced nephropathy (CIN). As tetramethylpyrazine (TMP) has been recently found to be renoprotective and anti-apoptotic in multiple kidney injuries, we hypothesized that TMP would prevent CIN. Methods: An experimental model of CIN was established in rats. Serum creatinine, blood urea nitrogen, plasma cystatin C, urinary N-acetyl-β-glucosaminidase, and urinary γ-glutamyl transpeptidase were measured to evaluate kidney function. Apoptosis was assessed by transmission electron microscopy, transferase-mediated deoxyuridine triphosphate nick end-labeling staining, and poly-ADP-ribose polymerase cleavage. Fork-head box O1 transcriptional factor (FoxO1) mRNA expression was evaluated by quantitative real-time PCR. Phospho-p38 mitogen-activated protein kinase (MAPK) protein expression was assessed by immunohistochemistry and Western blotting. Results: TMP significantly attenuated the resulting renal dysfunction and renal tubular cell apo-ptosis. Mechanistically, TMP decreased the expression of phospho-p38 MAPK protein and attenuated the increased FoxO1 mRNA and nuclear protein expression. In addition, TMP inhibited inducible nitric oxide synthase and Bax protein expression while it upregulated Bcl-2. Conclusion: In summary, this study demonstrated the protective role of TMP against CIN and indicated the effects of TMP may be mediated by the inhibition of p38 MAPK and FoxO1 pathways. Thus, TMP may be a new potential therapeutic agent to prevent CIN.

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FoxO Proteins Mediate Hypoxic Induction of Connective Tissue Growth Factor in Endothelial Cells

Cited by 35 publications

References 43 publications

Metabolic zonation of the liver: The oxygen gradient revisited

Metabolic zonation of the liver: The oxygen gradient revisited

CTGF is a therapeutic target for metastatic melanoma

Tetramethylpyrazine Prevents Contrast-Induced Nephropathy by Inhibiting p38 MAPK and FoxO1 Signaling Pathways

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