FMRP regulates endothelial cell proliferation and angiogenesis via the miR‐181a‐CaM‐CaMKII pathway

Zhao, Xin; Wang, Yang; Meng, Chao; Fang, Ningyuan

doi:10.1002/cbin.11039

Cited by 16 publications

(8 citation statements)

References 29 publications

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“…Interestingly, this protein is a tumor suppressor with angiogenic properties, as demonstrated in rat 3Y1 cells transformed with v-src by reducing VEGF expression, and hence cell proliferation and cell motility [214]. Finally, in connection with the function of CaM in angiogenesis it is worth mentioning that the anti-angiogenic action of TNF-α is due to FMRP (fragile X chromosome mental retardation protein) dephosphorylation, facilitating in this manner the expression of miR-181a, a microRNA that blocks CaM translation, therefore preventing CaMK-II activation [215].…”

Section: Calmodulin-regulated Proteins In Cell Invasion and Metastasismentioning

confidence: 98%

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

Villalobo

Berchtold

2020

IJMS

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Calmodulin (CaM) is the principal Ca2+ sensor protein in all eukaryotic cells, that upon binding to target proteins transduces signals encoded by global or subcellular-specific changes of Ca2+ concentration within the cell. The Ca2+/CaM complex as well as Ca2+-free CaM modulate the activity of a vast number of enzymes, channels, signaling, adaptor and structural proteins, and hence the functionality of implicated signaling pathways, which control multiple cellular functions. A basic and important cellular function controlled by CaM in various ways is cell motility. Here we discuss the role of CaM-dependent systems involved in cell migration, tumor cell invasiveness, and metastasis development. Emphasis is given to phosphorylation/dephosphorylation events catalyzed by myosin light-chain kinase, CaM-dependent kinase-II, as well as other CaM-dependent kinases, and the CaM-dependent phosphatase calcineurin. In addition, the role of the CaM-regulated small GTPases Rac1 and Cdc42 (cell division cycle protein 42) as well as CaM-binding adaptor/scaffold proteins such as Grb7 (growth factor receptor bound protein 7), IQGAP (IQ motif containing GTPase activating protein) and AKAP12 (A kinase anchoring protein 12) will be reviewed. CaM-regulated mechanisms in cancer cells responsible for their greater migratory capacity compared to non-malignant cells, invasion of adjacent normal tissues and their systemic dissemination will be discussed, including closely linked processes such as the epithelial–mesenchymal transition and the activation of metalloproteases. This review covers as well the role of CaM in establishing metastatic foci in distant organs. Finally, the use of CaM antagonists and other blocking techniques to downregulate CaM-dependent systems aimed at preventing cancer cell invasiveness and metastasis development will be outlined.

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Section: Calmodulin-regulated Proteins In Cell Invasion and Metastasismentioning

confidence: 98%

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

Villalobo

Berchtold

2020

IJMS

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“…A complete gene analysis showed that cell cluster #9 upregulated several known pro-angiogenic genes and transcription factors that are expressed in mesenchymal stromal cells (Sca-1/Ly6A, Ccl2, Ankrd1, Nfe2l1; Figures 4 H–4K and S7 ). 28 , 29 , 30 In addition, we saw elevated Fmr1, which regulates endothelial cell proliferation and angiogenesis, 31 and higher Zc3 h15 expression that correlates with expression of the pro-angiogenic protein a-fetoprotein (AFP). 32 , 33 Taken together, these results suggest the 7G-modRNA cocktail’s beneficial mechanism of action may occur via angiogenesis and paracrine effects to induce cardiovascular regeneration post MI.…”

Section: Resultsmentioning

confidence: 91%

Direct reprogramming induces vascular regeneration post muscle ischemic injury

et al. 2021

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“…There is also evidence that miRNAs play a regulatory role in aberrant CaM/CaMKII cascades in ischemia and reperfusion. For example, miR-181a has been shown to participate in the CaM/CaMKII pathway during the action of the Fragile X mental retardation protein in controlling the proliferation and angiogenesis of human umbilical vein endothelial cells ( 32 ). CaM and CaMKII expression is affected at the post-transcriptional level by miR-26b ( 33 ), miR-145 ( 34 ), and miR-148a ( 35 ), thereby contributing to the progression of ischemic injury.…”

Section: Introductionmentioning

confidence: 99%

Tilianin improves cognition in a vascular dementia rodent model by targeting miR-193b-3p/CaM- and miR-152-3p/CaMKIIα-mediated inflammatory and apoptotic pathways

et al. 2023

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IntroductionAlthough vascular dementia (VaD) is the second most prevalent form of dementia, there is currently a lack of effective treatments. Tilianin, isolated from the traditional drug Dracocephalum moldavica L., may protect against ischemic injury by inhibiting oxidative stress and inflammation via the CaMKII-related pathways but with weak affinity with the CaMKII molecule. microRNAs (miRNAs), functioning in post-transcriptional regulation of gene expression, may play a role in the pathological process of VaD via cognitive impairment, neuroinflammatory response, and neuronal dysfunction. This study aimed to investigate the role of tilianin in VaD therapy and the underlying mechanism through which tilianin regulates CaMKII signaling pathways based on miRNA-associated transcriptional action.MethodsRats with 2-vessel occlusion (2VO), a standard model of VaD, were treated with tilianin, vehicle control, and target overexpression or downregulation. High-throughput sequencing, qRT-PCR, and western blot analyses were utilized to identify the downstream target genes and signaling pathways of tilianin involved in VaD.ResultsOur results showed that tilianin ameliorated cognitive deficits, neurodegeneration, and microglial and astrocytic activation in rats with 2VO. Subsequent high-throughput sequencing and qRT-PCR analyses revealed that tilianin increased the downregulated miR-193b-3p and miR-152-3p levels in the cortex and hippocampus of 2VO rats. Mechanistically, miR-193b-3p targeting CaM and miR-152-3p targeting CaMKIIα were identified to play a role in VaD-associated pathology, inhibiting the p38 MAPK/NF--κB p65 pathway and decreasing TNF-α and IL-6 levels. Further gain- and loss-of-function experiments for these key genes showed that tilianin-exerted cognitive improvement by activating the p38 MAPK/NF--κB p65 and Bcl-2/Bax/caspase-3/PARP pathways in the brain of 2VO rats was abolished by miR-193b-3p and miR-152-3p inhibition. Moreover, CaM and CaMKIIα overexpression eliminated the elevated effects of miR-193b-3p and miR-152-3p on tilianin’s protection against ischemic injury through increased inflammatory reactions and apoptotic signaling.DiscussionTogether, these findings indicate that tilianin improves cognition by regulating the miR-193b-3p/CaM- and miR-152-3p/CaMKIIα-mediated inflammatory and apoptotic pathways, suggesting a potential small-molecule regulator of miRNA associated with inflammatory signaling for VaD treatment.

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FMRP regulates endothelial cell proliferation and angiogenesis via the miR‐181a‐CaM‐CaMKII pathway

Cited by 16 publications

References 29 publications

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

Direct reprogramming induces vascular regeneration post muscle ischemic injury

Tilianin improves cognition in a vascular dementia rodent model by targeting miR-193b-3p/CaM- and miR-152-3p/CaMKIIα-mediated inflammatory and apoptotic pathways

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