Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations

Zhu, Yuan; Wu, Qun; Xu, Jinfang; Miller, Dorothea; Sandalcioglu, I. Erol; Zhang, Jianmin; Sure, Ulrich

doi:10.3171/2010.5.focus1090

Cited by 69 publications

(71 citation statements)

References 31 publications

(47 reference statements)

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“…For example, Rac1 contributes to EGF-induced phosphorylation of p38 in papilloma cells but not in normal laryngeal cells (20). Furthermore, similar to our finding, knockdown of OSM in human endothelial cells increases phosphorylation of p38 (21).…”

Section: Discussionsupporting

confidence: 79%

Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-γ1 to activation of the osmoprotective transcription factor NFAT5

Zhou

Yokoyama

Burg

et al. 2011

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

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Separate reports that hypertonicity activates p38 via a Rac1-OSM-MEKK3-MKK3-p38 pathway and that p38α contributes to activation of TonEBP/OREBP led us to the hypothesis that Rac1 might activate TonEBP/OREBP via p38. The present studies examine that possibility. High NaCl is hypertonic. We find that siRNA knockdown of Rac1 reduces high NaCl-induced increase of TonEBP/OREBP transcriptional activity (by reducing its transactivating activity but not its nuclear localization). Similarly, siRNA knockdown of osmosensing scaffold for MEKK3 (OSM) also reduces high NaCl-dependent TonEBP/OREBP transcriptional and transactivating activities. Simultaneous siRNA knockdown of Rac1 and OSM is not additive in reduction of TonEBP/OREBP transcriptional activity, indicating a common pathway. However, siRNA knockdown of MKK3 does not reduce TonEBP/OREBP transcriptional activity, although siRNA knockdown of MKK6 does. Nevertheless, the effect of Rac1 on TonEBP/OREBP is also independent of MKK6 because it occurs in MKK6-null cells. Furthermore, we find that siRNA knockdown of Rac1 or OSM actually increases activity (phosphorylation) of p38, rather than decreasing it, as previously reported. Thus, the effect of Rac1 on TonEBP/OREBP is independent of p38. We find instead that phospholipase C-γ1 (PLC-γ1) is involved. When transfected into PLC-γ1-null mouse embryonic fibroblast cells, catalytically active Rac1 does not increase TonEBP/OREBP transcriptional activity unless PLC-γ1 is reconstituted. Similarly, dominant-negative Rac1 also does not inhibit TonEBP/OREBP in PLC-γ1-null cells unless PLC-γ1 is reconstituted. We conclude that Rac1/OSM supports TonEBP/ OREBP activity and that this activity is mediated via PLC-γ1, not p38. osmotic stress | MAPK H ypertonicity (e.g., high NaCl) activates the transcription factor TonEBP/OREBP (also known as NFAT5), resulting in increased expression of osmoprotective genes (1). Hypertonicity increases TonEBP/OREBP activity by increasing its abundance (1), transactivating activity (1), nuclear localization (1), and phosphorylation (2, 3). The regulatory increase of phosphorylation depends on both increased kinase activity and reduced phosphatase activity (4, 5). The stress-activated MAP kinase p38 has been extensively studied in this regard, but understanding its role has been complicated because hypertonicity activates two different p38s, namely p38α (MAPK14) and p38δ (MAPK13), which have opposite effects on TonEBP/OREBP activity: p38α increases TonEBP/OREBP activity and p38δ decreases it (6). Furthermore, the phosphospecific antibodies commonly used to measure p38 activity do not directly distinguish between p38α activity and p38δ activity, nor do some forms of inhibition that have been used (6). In this article, we will continue to refer to "p38" unless p38α and p38δ are distinguished. Hypertonicity activates p38α via the upstream kinase MKK3 (MAP2K3) or MKK6 (MAP2K6) (7), and p38α and MEKK3 (MAP3K3) contribute to hypertonicity-induced activation of TonEBP/OREBP (6, 8, 9). Thus, p38α contributes to To...

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Section: Discussionsupporting

confidence: 79%

Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-γ1 to activation of the osmoprotective transcription factor NFAT5

Zhou

Yokoyama

Burg

et al. 2011

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

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“…Furthermore, we show that loss of KRIT1 increases cell migration, which has been reported in PDCD10-, but not CCM2-, deficient cells (60). The activation of nuclear ␤-catenin signaling in both Krit1-and PDCD10-depleted endothelial cells led to an increase in Vegfa mRNA.…”

Section: Discussionsupporting

confidence: 77%

“…In zebrafish, PDCD10 deficiency causes heart and circulation effects distinct from those seen in Krit1 and CCM2 mutants (59). Then again, loss of CCM2 or PDCD10, but not KRIT1, activate p38 and Akt (51,60), challenging the idea that loss of PDCD10 promotes CCM formation via an independent mechanism.…”

Section: Discussionmentioning

confidence: 99%

KRIT1 Protein Depletion Modifies Endothelial Cell Behavior via Increased Vascular Endothelial Growth Factor (VEGF) Signaling

DiStefano

Kuebel

Sarelius

et al. 2014

Journal of Biological Chemistry

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Background: Loss of Krev-interaction trapped 1 (KRIT1) drives the activation of endothelial cells. Results: Blocking vascular endothelial growth factor (VEGF) signaling reverses the endothelial cell changes after KRIT1 depletion and permeability in KRIT1-deficient mice. Conclusion: Increased VEGF signaling downstream of KRIT1 loss alters endothelial cell behavior and is responsible for permeability in vivo. Significance: These studies describe a novel regulation of endothelial barrier function by KRIT1.

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“…PDCD10 (also known as cerebral cavernous malformation 3, CCM3) was expressed in endothelial cells and was essential for vascular development (28). Previous results showed silencing CCM3 or loss of CCM3 (decreased expression of CCM3) stimulated sprouting and tube branching or activated endothelial angiogenesis (29)(30)(31). These data indicated the roles of PDCD10 as an anti-angiogenic transcription factor in vascular development/maturation.…”

Section: Discussionmentioning

confidence: 85%

Hypoxia-induced miR-181b enhances angiogenesis of retinoblastoma cells by targeting PDCD10 and GATA6

Jia

et al. 2015

Oncology Reports

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Abstract. Previous findings showed that miR-181b is upregulated under hypoxic conditions in retinoblastoma cells. Since hypoxia is a common feature of retinoblastoma that affects tumor progression as well as tumor therapy, in the present study, we investigated the regulatory mechanism of miR-181b under hypoxic conditions, and examined the role of miR-181b in retinoblastoma responses to hypoxia (chemoresistance and angiogenesis) and possible downstream genes. The level of hypoxia-inducible factor-1α (HIF-1α) and miR-181b was detected to examine the link between them. Tube formation and cell cytotoxicity assays were used to clarify the effects of miR-181b on hypoxic responses of retinoblastoma cells. Bioinformatics analysis was performed to predict potential targets of miR-181b and western blotting was used to verify these targets. The results showed a significantly increased expression of HIF-1α in hypoxia-treated retinoblastoma cells. Downregulation of HIF-1α using a small-interfering RNA (siRNA) knockdown technology did not decrease the expression of miR-181b. Through gain-and loss-of-function studies, miR-181b was demonstrated to significantly stimulate the ability of capillary tube formation of endothelial cells. Programmed cell death-10 (PDCD10) and GATA binding protein 6 (GATA6) were identified as the target genes of miR-181b. To the best of our knowledge, results of the present study provide the first evidence that miR-181b was upregulated by hypoxia in retinoblastoma in an HIF-1α-independent manner. miR-181b increased tumor angiogenesis of retinoblastoma cells. Additionally, miR-181b exerts its angiogenic function, at least in part, by inhibiting PDCD10 and GATA6. Thus, it is a new potentially useful therapeutic target for retinoblastoma.

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Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations

Cited by 69 publications

References 31 publications

Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-γ1 to activation of the osmoprotective transcription factor NFAT5

Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-γ1 to activation of the osmoprotective transcription factor NFAT5

KRIT1 Protein Depletion Modifies Endothelial Cell Behavior via Increased Vascular Endothelial Growth Factor (VEGF) Signaling

Hypoxia-induced miR-181b enhances angiogenesis of retinoblastoma cells by targeting PDCD10 and GATA6

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