Apoptotic Functions of
            <i>PDCD10/CCM3</i>
            , the Gene Mutated in Cerebral Cavernous Malformation 3

Chen, Leiling; Tanrıöver, Gamze; Yano, Hiroko; Friedlander, Robert M; Louvi, Angeliki; Günel, Murat

doi:10.1161/strokeaha.108.527135

Cited by 79 publications

(58 citation statements)

References 44 publications

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“…25 The different studies also showed various regulations of p38 activation in response to CCM3 silencing. 5,14 These data suggest that CCM genes trigger cellular signaling pathways in a cell typespecific manner. We demonstrated that CCM2 or CCM3 silencing commonly activated p38, ERK1/2, and Akt in CCM-ECs, consistent with the current opinion that these 3 CCM genes interact as an intracellular complex and share some common signaling pathways.…”

Section: Discussionmentioning

confidence: 84%

“…17 Although this proposal remains speculative, one could imagine that the endothelium in CCM lesions harbors certain unique properties because the lesions have been exposed to this abnormal, yet undefined, microenvironment. Within this context and considering that the functional study of CCM genes in culture has been performed exclusively in cell lines 3,5,6,14 or in commercially purchased normal ECs (HUVECs and HBMECs), 6,25 silencing CCM genes in CCM-ECs established in the present work may simulate some aspects of the diseased endothelium in the CCM lesions, and thus may serve as a unique and valuable model for investigating the function of CCM genes in the pathogenesis of CCMs.…”

Section: Discussionmentioning

confidence: 99%

“…8,24 The role of CCM2 in maintenance of vascular integrity has been proposed through regulating the activity of Ras homolog gene family member A. The mechanism of this regulation has been recently addressed by Crose et al 6 The CCM3 gene is suggested to be involved in apoptosis 5,14 and tumor signaling. 14 We found that loss of CCM3 led to a significant resistance of all 3 tested types of ECs to apoptotic stimuli (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations

Zhu

et al. 2010

FOC

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Object Loss-of-function mutations in CCM genes are frequently detected in familial cerebral cavernous malformations (CCMs). However, the current functional studies of the CCM genes in vitro have been performed mostly in commercially purchased normal cell lines and the results appeared discrepant. The fact that the cerebral vascular defects are rarely observed in CCM gene-deficient animals suggests the requirement of additional pathological background for the formation of vascular lesions. Consistent with these data, the authors assumed that silencing CCM genes in the endothelium derived from CCMs (CCM-ECs) serves as a unique and valuable model for investigating the function of the CCM genes in the pathogenesis of CCMs. To this end, the authors investigated the role and signaling of CCM2 and CCM3 in the key steps of angiogenesis using CCM-ECs. Methods Endothelial cells (ECs) derived from CCMs were isolated, purified, and cultured from the fresh operative specimens of sporadic CCMs (31 cases). The CCM2 and CCM3 genes were silenced by the specific short interfering RNAs in CCM-ECs and in control cultures (human brain microvascular ECs and human umbilical vein ECs). The efficiency of gene silencing was proven by real-time reverse transcriptase polymerase chain reaction. Cell proliferation and apoptosis, migration, tube formation, and the expression of phosphor-p38, phosphor-Akt, and phosphor-extracellular signal-regulated kinase–1 and 2 (ERK1/2) were analyzed under CCM2 and CCM3 silenced conditions in CCM-ECs. Results The CCM3 silencing significantly promoted proliferation and reduced apoptosis in all 3 types of endothelium, but accelerated cell migration exclusively in CCM-ECs. Interestingly, CCM2 siRNA influenced neither cell proliferation nor migration. Silencing of CCM3, and to a lesser extent CCM2, stimulated the growth and extension of sprouts selectively in CCM-ECs. Loss of CCM2 or CCM3 did not significantly influence the formation of the tubelike structure. However, the maintenance of tube stability was largely impaired by CCM2, but not CCM3, silencing. Western blot analysis revealed that CCM2 and CCM3 silencing commonly activated p38, Akt, and ERK1/2 in CCM-ECs. Conclusions The unique response of CCM-ECs to CCM2 or CCM3 siRNA indicates that silencing CCM genes in CCM-ECs is valuable for further studies on the pathogenesis of CCMs. Using this model system, the authors demonstrate a distinct role of CCM2 and CCM3 in modulating the different processes of angiogenesis. The stimulation of endothelial proliferation, migration, and massively growing and branching angiogenic sprouts after CCM3 silencing may potentially contribute to the formation of enriched capillary-like immature vessels in CCM lesions. The severe impairment of the tube integrity by CCM2, but not CCM3, silencing is associated with the different intracranial hemorrhage rate observed from CCM2 and CCM3 mutation carriers. The activation of p38, ERK1/2, and Akt signal proteins in CCM2- or CCM3-silenced CCM-ECs suggests a possible involvement of these common pathways in the pathogenesis of CCMs. However, the specific signaling mediating the distinct function of CCM genes in the pathogenesis of CCMs needs to be further elucidated.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations

Zhu

et al. 2010

FOC

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“…84 Multiple meningiomas have been observed in patients with mutations in CCM3/PDCD10, a gene associated with cerebral cavernous malformations that contributes to proliferation and resistance to apoptosis via activation of AKT signaling, 20,48,56,75 and the SUFU gene, which regulates hedgehog signaling.…”

Section: Other Germline Syndromesmentioning

confidence: 99%

Genomic landscape of intracranial meningiomas

Abedalthagafi

Horowitz

et al. 2016

JNS

104

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M eningioMas are the most common primary intracranial neoplasms in adults, accounting for 35.8% of all primary CNS tumors and more than 53% of all benign CNS tumors diagnosed in the US. 65 Autopsy and imaging studies suggest an even higher prevalence, affecting almost 3% of women.98 These lesions are believed to arise from progenitor cells that give rise to both the arachnoid cap cells of the arachnoid layer and fibroblasts that reside in the inner dura mater. 18,45The vast majority of meningiomas are indolent.36 A small percentage, however, display malignant behavior characterized by invasive growth patterns and/or markedly higher recurrence rates. Notably, even meningiomas that lack histological features of malignancy recur at significant rates. Multimodality therapy including surgery and radiation is often used in the management of these subsets of meningioma, but other therapeutic modalities have failed to improve control rates. Aggressive meningiomas and the meningiomatosis that occur in hereditary syndromes remain difficult clinical problems. Although most meningiomas are "benign," there is substantial morbidity associated with recurrence, and clinical management remains challenging for clinicians worldwide.Unbiased genome-and exome-wide sequencing approaches have implicated a central core of gene mutations that are associated with a substantial percentage of these tumors. This information may highlight therapeutic targets and enhance biological classification of meningioma. 12,22 Just as an improved understanding of genomic alterations has changed the way we classify and treat cancers including chronic myelogenous leukemia, melanoma, and lung cancer, similar interrogation of the meningioma genome has revealed potential novel treatment pathways for patients harboring these tumors. Meningiomas are the most common primary intracranial neoplasms in adults. Current histopathological grading schemes do not consistently predict their natural history. Classic cytogenetic studies have disclosed a progressive course of chromosomal aberrations, especially in high-grade meningiomas. Furthermore, the recent application of unbiased nextgeneration sequencing approaches has implicated several novel genes whose mutations underlie a substantial percentage of meningiomas. These insights may serve to craft a molecular taxonomy for meningiomas and highlight putative therapeutic targets in a new era of rational biology-informed precision medicine.

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“…CCM3, however, has also been identified as part of an additional multiprotein complex that includes all three members of the germinal center kinase III (GCK-III) family of Ste20 kinases [serine/threonine kinase (Stk) 24, Stk25, and Mst4] (23), possibly promoting assembly of the Golgi apparatus (24). Interestingly, many components of this complex are involved in cell cycle regulation and apoptosis, with CCM3 having a proapoptotic role in vitro (25). Finally, global or endothelial deletion of Ccm3 causes embryonic lethality associated with defects in vascular development and VEGF receptor 2 (VEGFR2) signaling (26), and in zebrafish, CCM3-mediated signaling through Ste20-like kinases is involved in cardiovascular development (27).…”

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confidence: 99%

Loss of cerebral cavernous malformation 3 ( Ccm3 ) in neuroglia leads to CCM and vascular pathology

Louvi¹,

Chen²,

Two³

et al. 2011

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

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Communication between neural cells and the vasculature is integral to the proper development and later function of the central nervous system. A mechanistic understanding of the interactions between components of the neurovascular unit has implications for various disorders, including cerebral cavernous malformations (CCMs) in which focal vascular lesions form throughout the central nervous system. Loss of function mutations in three genes with proven endothelial cell autonomous roles, CCM1/krev1 interaction trapped gene 1, CCM2, and CCM3/programmed cell death 10, cause familial CCM. By using neural specific conditional mouse mutants, we show that Ccm3 has both neural cell autonomous and nonautonomous functions. Gfap-or Emx1-Cre-mediated Ccm3 neural deletion leads to increased proliferation, increased survival, and activation of astrocytes through cell autonomous mechanisms involving activated Akt signaling. In addition, loss of neural CCM3 results in a vascular phenotype characterized by diffusely dilated and simplified cerebral vasculature along with formation of multiple vascular lesions that closely resemble human cavernomas through cell nonautonomous mechanisms. RNA sequencing of the vascular lesions shows abundant expression of molecules involved in cytoskeletal remodeling, including protein kinase A and Rho-GTPase signaling. Our findings implicate neural cells in the pathogenesis of CCMs, showing the importance of this pathway in neural/vascular interactions within the neurovascular unit. cerebrovascular disease | activated astrocytes | animal models

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Apoptotic Functions of PDCD10/CCM3 , the Gene Mutated in Cerebral Cavernous Malformation 3

Cited by 79 publications

References 44 publications

Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations

Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations

Genomic landscape of intracranial meningiomas

Loss of cerebral cavernous malformation 3 ( Ccm3 ) in neuroglia leads to CCM and vascular pathology

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