Loss of WNK2 expression by promoter gene methylation occurs in adult gliomas and triggers Rac1-mediated tumour cell invasiveness

Moniz, Sónia; Martinho, Olga; Pinto, Filipe; Sousa, Bárbara; Loureiro, Cláudia; Oliveira, Maria José; Moita, Luís F.; Honavar, Mrinalini; Pinheiro, Célia; Pires, Manuel Melo; Lopes, José Manuel; Jones, Chris; Costello, J; Paredes, Joana; Reis, Rui Manuel; Jordan, Peter

doi:10.1093/hmg/dds405

Cited by 44 publications

(54 citation statements)

References 39 publications

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“…WNKs 1, 2, and 3 have also been shown to regulate migration (63)(64)(65). We find that WNK1 is required for endothelial cell migration toward a chemoattractant that is dependent on OSR1 but not SPAK.…”

Section: Discussionmentioning

confidence: 66%

Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK

Dbouk

Weil

Perera

et al. 2014

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

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The with no lysine (K) (WNK) family of enzymes is best known for control of blood pressure through regulation of the function and membrane localization of ion cotransporters. In mice, global as well as endothelial-specific WNK1 gene disruption results in embryonic lethality due to angiogenic and cardiovascular defects. WNK1−/− embryos can be rescued by endothelial-specific expression of a constitutively active form of the WNK1 substrate protein kinase OSR1 (oxidative stress responsive 1). Using human umbilical vein endothelial cells (HUVECs), we explored mechanisms underlying the requirement of WNK1-OSR1 signaling for vascular development. WNK1 is required for cord formation in HUVECs, but the actions of the two major WNK1 effectors, OSR1 and its close relative SPAK (STE20/SPS1-related proline-, alanine-rich kinase), are distinct. SPAK is important for endothelial cell proliferation, whereas OSR1 is required for HUVEC chemotaxis and invasion. We also identified the zinc-finger transcription factor Slug in WNK1-mediated control of endothelial functions. Our study identifies a separation of functions for the WNK1-activated protein kinases OSR1 and SPAK in mediating proliferation, invasion, and gene expression in endothelial cells and an unanticipated link between WNK1 and Slug that is important for angiogenesis.endothelium | angiogenesis | migration | EMT | Slug

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Section: Discussionmentioning

confidence: 66%

Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK

Dbouk

Weil

Perera

et al. 2014

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

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“…It plays crucial roles in signal transduction pathway that control proliferation, adhesion, and migration of cells during embryonic development, invasiveness of tumour cells (Jin et al, 2007) as well as apoptosis (Sun et al, 2006). The expression of RAC1 is important for cell growth, motility and morphology in glioma cells (Hu et al, 2009;Moniz et al, 2013). Blockade of RAC1 signalling in tissue remodelling promotes the accumulation of type I collagen due to decreased collagenase activity (Igata et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Expression Profile of Genes Modulated by Aloe emodin in Human U87 Glioblastoma Cells

Haris

Ismail²,

Idris³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Glioblastoma, the most aggressive and malignant form of glioma, appears to be resistant to various chemotherapeutic agents. Hence, approaches have been intensively investigated to targeti specific molecular pathways involved in glioblastoma development and progression. Aloe emodin is believed to modulate the expression of several genes in cancer cells. We aimed to understand the molecular mechanisms underlying the therapeutic effect of Aloe emodin on gene expression profiles in the human U87 glioblastoma cell line utilizing microarray technology. The gene expression analysis revealed that a total of 8,226 gene alterations out of 28,869 genes were detected after treatment with 58.6 µg/ml for 24 hours. Out of this total, 34 genes demonstrated statistically significant change (p<0.05) ranging from 1.07 to 1.87 fold. The results revealed that 22 genes were up-regulated and 12 genes were down-regulated in response to Aloe emodin treatment. These genes were then grouped into several clusters based on their biological functions, revealing induction of expression of genes involved in apoptosis (programmed cell death) and tissue remodelling in U87 cells (p<0.01). Several genes with significant changes of the expression level e.g. SHARPIN, BCAP31, FIS1, RAC1 and TGM2 from the apoptotic cluster were confirmed by quantitative real-time PCR (qRT-PCR). These results could serve as guidance for further studies in order to discover molecular targets for the cancer therapy based on Aloe emodin treatment.

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“…32,33,37 Gene expression was validated by PCR in HD B-cell samples as well as in MYD88 and CXCR4 genotyped WM patient samples (supplemental Figure 4A). …”

Section: Promoter Methylation Studiesmentioning

confidence: 99%

Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia

Hunter

Liu

Yang

et al. 2016

Blood

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• Transcription profiles associated with mutated MYD88, CXCR4, ARID1A, abnormal cytogenetics including 6q2, and familial WM are described.• Mutated CXCR4 profiles show impaired expression of the tumor suppressor response induced by MYD88 L265P and also G-protein/MAPK inhibitors.Whole-genome sequencing has identified highly prevalent somatic mutations including MYD88, CXCR4, and ARID1A in Waldenström macroglobulinemia (WM). The impact of these and other somatic mutations on transcriptional regulation in WM remains to be clarified. We performed next-generation transcriptional profiling in 57 WM patients and compared findings to healthy donor B cells. Compared with healthy donors, WM patient samples showed greatly enhanced expression of the VDJ recombination genes DNTT, RAG1, and RAG2, but not AICDA. Genes related to CXCR4 signaling were also upregulated and included CXCR4, CXCL12, and VCAM1 regardless of CXCR4 mutation status, indicating a potential role for CXCR4 signaling in all WM patients. The WM transcriptional profile was equally dissimilar to healthy memory B cells and circulating B cells likely due increased differentiation rather than cellular origin. The profile for CXCR4 mutations corresponded to diminished B-cell differentiation and suppression of tumor suppressors upregulated by MYD88 mutations in a manner associated with the suppression of TLR4 signaling relative to those mutated for MYD88 alone. Promoter methylation studies of top findings failed to explain this suppressive effect but identified aberrant methylation patterns in MYD88 wild-type patients. CXCR4 and MYD88 transcription were negatively correlated, demonstrated allele-specific transcription bias, and, along with CXCL13, were associated with bone marrow disease involvement. Distinct gene expression profiles for patients with wild-type MYD88, mutated ARID1A, familial predisposition to WM, chr6q deletions, chr3q amplifications, and trisomy 4 are also described. The findings provide novel insights into the molecular pathogenesis and opportunities for targeted therapeutic strategies for WM. (Blood. 2016;128(6):827-838)

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Loss of WNK2 expression by promoter gene methylation occurs in adult gliomas and triggers Rac1-mediated tumour cell invasiveness

Cited by 44 publications

References 39 publications

Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK

Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK

Expression Profile of Genes Modulated by Aloe emodin in Human U87 Glioblastoma Cells

Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia

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