<scp>KLF</scp>
            4 is a key determinant in the development and progression of cerebral cavernous malformations

Cuttano, Roberto; Rudini, Noemi; Bravi, Luca; Corada, Monica; Giampietro, Costanza; Papa, Eleanna; Morini, Marco; Maddaluno, Luigi; Baeyens, Nicolas; Adams, Ralf H.; Jain, Mukesh Mk; Owens, Gary Gk; Schwartz, Martin A.; Lampugnani, Maria Grazia; Dejana, Elisabetta

doi:10.15252/emmm.201505433

Cited by 153 publications

(194 citation statements)

References 95 publications

(135 reference statements)

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“…Loss-of-function of CCM proteins has also been shown to trigger β-catenin and transforming growth factor beta/bone morphogenetic protein (TGFβ/BMP) signaling-driven endothelial-to-mesenchymal transition (EndMT) (Bravi et al, 2016, Bravi et al, 2015, Guan and Couldwell, 2013, Maddaluno et al, 2013), as well as activation of MEKK3 signaling and increased expression of the mechanosensitive transcription factors KLF2 and KLF4 (Cullere et al, 2015, Cuttano et al, 2016, Fisher et al, 2015; Zhou et al, 2015; Zhou et al, 2016). Both of these mechanisms have been suggested to be key determinants of CCM disease pathogenesis (Maddaluno et al, 2013, Bravi et al, 2016, Cuttano et al, 2016, Zhou et al, 2016).…”

Section: Current Knowledge Of the Molecular Basis And Mechanisms Of Cmentioning

confidence: 99%

“…Both of these mechanisms have been suggested to be key determinants of CCM disease pathogenesis (Maddaluno et al, 2013, Bravi et al, 2016, Cuttano et al, 2016, Zhou et al, 2016). Moreover, it has been also suggested that increased Rho activity, as well as proteolytic activity of extracellular matrix metalloprotease ADAMTS, arises secondary to increased MEKK3–KLF2/4 signaling during CCM formation (Zhou et al, 2016).…”

Section: Current Knowledge Of the Molecular Basis And Mechanisms Of Cmentioning

confidence: 99%

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Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Retta

Glading

2016

The International Journal of Biochemistry & Cell Biology

110

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Graphical abstractTowards a unifying mechanism for CCM disease pathogenesis and treatment.CCM proteins play pleiotropic roles in distinct redox-sensitive pathways by modulating the fine-tuned crosstalk between redox signaling and autophagy. Effective autophagy removes ROS-generating cellular trash, including damaged mitochondria, to rejuvenate cell environment, thus serving a cytoprotective function for the maintenance of endothelial cell monolayer integrity and functionality and blood–brain barrier (BBB) stability even under adverse stress conditions. Loss-of-function of a CCM protein (e.g., KRIT1) causes defective autophagy and altered redox signaling, affecting BBB stability and sensitizing endothelial cells to local oxidative stress and inflammatory events, which may act as key pathogenic determinants of focal formation and progression of CCM lesions. The common capacity to modulate the interplay between autophagy and redox signaling reconciles the distinct pharmacological approaches proposed so far for CCM disease prevention and treatment.

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Section: Current Knowledge Of the Molecular Basis And Mechanisms Of Cmentioning

confidence: 99%

Section: Current Knowledge Of the Molecular Basis And Mechanisms Of Cmentioning

confidence: 99%

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Retta

Glading

2016

The International Journal of Biochemistry & Cell Biology

110

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“…5 A′′-F′′ and U). Previous work showed that KLF2/4 are up-regulated following CCM loss in endothelial cells (29)(30)(31)(32)(33). KLF2/4 signals were increased in the cerebellum of cKO mice, but the drugs did not reverse this effect (Fig.…”

Section: Combined Treatment Reverses Outcomes Of Endothelial Ccm3 Losmentioning

confidence: 80%

Combined HMG-COA reductase and prenylation inhibition in treatment of CCM

Nishimura

Mishra-Gorur

Park

et al. 2017

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

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Cerebral cavernous malformations (CCMs) are common vascular anomalies that develop in the central nervous system and, more rarely, the retina. The lesions can cause headache, seizures, focal neurological deficits, and hemorrhagic stroke. Symptomatic lesions are treated according to their presentation; however, targeted pharmacological therapies that improve the outcome of CCM disease are currently lacking. We performed a high-throughput screen to identify Food and Drug Administration-approved drugs or other bioactive compounds that could effectively suppress hyperproliferation of mouse brain primary astrocytes deficient for CCM3. We demonstrate that fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase and the N-bisphosphonate zoledronic acid monohydrate, an inhibitor of protein prenylation, act synergistically to reverse outcomes of CCM3 loss in cultured mouse primary astrocytes and in Drosophila glial cells in vivo. Further, the two drugs effectively attenuate neural and vascular deficits in chronic and acute mouse models of CCM3 loss in vivo, significantly reducing lesion burden and extending longevity. Sustained inhibition of the mevalonate pathway represents a potential pharmacological treatment option and suggests advantages of combination therapy for CCM disease.cerebral cavernous malformations | fluvastatin | zoledronic acid | mevalonate pathway | high-throughput screen C erebral cavernous malformations (CCMs) are common vascular malformations that develop in the brain, spinal cord, and, more rarely, the retina (1, 2). The lesions consist of dilated sinusoidal channels lined with a single layer of endothelium devoid of vessel wall elements. CCM disease is often asymptomatic, but on occasion the lesions rupture leading to hemorrhagic stroke. Other common symptoms are headache, seizures, and focal neurological deficits. Treatment options include observation of asymptomatic lesions, antiepileptic medication, and surgical excision of lesions in patients with symptomatic or repetitive hemorrhages or intractable seizures; however pharmacological therapies that improve outcome are lacking. CCM disease is usually sporadic, although 20% of patients carry lossof-function mutations in one of three genes: CCM1 (also known as "KRIT1"), CCM2, and CCM3 (also known as "PDCD10") (3), which encode structurally unrelated cytoplasmic proteins with critical roles in endothelial cells (4) and, uniquely for CCM3, in neurons and astrocytes as well (5, 6). CCM3 loss in neural progenitors results in hyperproliferation/activation of brain astrocytes and enhanced activity of RhoA in vivo and increased proliferation and survival of primary astrocytes in vitro (5, 6). We took advantage of these well-defined cellular phenotypes of CCM3 loss to explore potential pharmacological treatment options for CCM. High-throughput screening of available drugs identified fluvastatin, a 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor as a top candidate. In combination with the N-bisphosphonate zoledronic acid monohyd...

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“…Mutations of the CCM3 gene have been linked to cerebral cavernous malformations -vascular abnormalities characterised by dilated leaky cerebral lesions that can lead to brain haemorrhage (Draheim et al, 2014). The exact mechanism by which cerebral cavernous malformations arise is still subject to debate, with deregulation of several signalling pathways such as RHO (Richardson et al, 2013;Stockton et al, 2010;Borikova et al, 2010;Whitehead et al, 2009), TGFβ (Maddaluno et al, 2013), β-catenin (Bravi et al, 2015) and MEKK3-KLF2 or MEKK3-KLF4 (Cuttano et al, 2016;Zhou et al, 2016;Renz et al, 2015) having been demonstrated to be involved in development and progression of the disease. Crucially, loss of the CCM3 interaction with GCKIII kinases seems to be the crucial feature of all disease-associated CCM3 mutations (Fidalgo et al, 2010).…”

Section: E-2mentioning

confidence: 99%

RHO binding to FAM65A regulates Golgi reorientation during cell migration

Mardakheh¹,

Self²,

Marshall³

2017

Development

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Directional cell migration involves reorientation of the secretory machinery. However, the molecular mechanisms that control this reorientation are not well characterised. Here, we identify a new Rho effector protein, named FAM65A, which binds to active RHOA, RHOB and RHOC. FAM65A links RHO proteins to Golgi-localising cerebral cavernous malformation-3 protein (CCM3; also known as PDCD10) and its interacting proteins mammalian STE20-like protein kinases 3 and 4 (MST3 and MST4; also known as STK24 and STK26, respectively). Binding of active RHO proteins to FAM65A does not affect the kinase activity of MSTs but results in their relocation from the Golgi in a CCM3-dependent manner. This relocation is crucial for reorientation of the Golgi towards the leading edge and subsequent directional cell migration. Our results reveal a previously unidentified pathway downstream of RHO that regulates the polarity of migrating cells through Golgi reorientation in a FAM65A-, CCM3-and MST3-and MST4-dependent manner.

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KLF 4 is a key determinant in the development and progression of cerebral cavernous malformations

Cited by 153 publications

References 95 publications

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Combined HMG-COA reductase and prenylation inhibition in treatment of CCM

RHO binding to FAM65A regulates Golgi reorientation during cell migration

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