Epigenetic Silencing of Stk39 in B-Cell Lymphoma Inhibits Apoptosis from Genotoxic Stress

Balatoni, Cynthia E.; Dawson, David W.; Suh, Jane; Sherman, Mara H.; Sanders, Grant; Hong, Jason; Frank, Matthew J.; Malone, Cindy S.; Said, Jonathan; Teitell, Michael A.

doi:10.2353/ajpath.2009.090091

Cited by 21 publications

(23 citation statements)

References 40 publications

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“…It is possible that SPAK may be involved in these actions in cell division that result in the slowed cell proliferation observed in WNK1 and SPAK knockdown HUVECs. This may also be related to the earlier finding that SPAK induces apoptosis in a caspase-dependent manner in response to genotoxic stress (62). Modulating SPAK activity directly or indirectly via WNK1 knockdown could lead to proliferation defects mediated by deregulation of cellular responses to DNA damage or other stress-induced apoptotic mechanisms.…”

Section: Discussionsupporting

confidence: 53%

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: Discussionsupporting

confidence: 53%

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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“…Polymorphisms in this gene have been linked to risk of hypertension (33-35). Epigenetic silencing of STK39 through DNA hypermethylation in B-cell lymphoma appears to promote cancer progression by inhibiting apoptosis in cells with DNA damage (36). …”

Section: Discussionmentioning

confidence: 99%

An epigenome-wide study of body mass index and DNA methylation in blood using participants from the Sister Study cohort

Wilson

Harlid

et al. 2016

Int J Obes

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Background/Objectives The relationship between obesity and chronic disease risk is well-established; the underlying biological mechanisms driving this risk increase may include obesity-related epigenetic modifications. To explore this hypothesis, we conducted a genome-wide analysis of DNA methylation and body mass index (BMI) using data from a subset of women in the Sister Study. Subjects/Methods The Sister Study is a cohort of 50,884 U.S. women who had a sister with breast cancer but were free of breast cancer themselves at enrollment. Study participants completed examinations which included measurements of height and weight, and provided blood samples. Blood DNA methylation data generated with the Illumina Infinium HumanMethylation27 BeadChip array covering 27,589 CpG sites was available for 871 women from a prior study of breast cancer and DNA methylation. To identify differentially methylated CpG sites associated with body mass index, we analyzed this methylation data using robust linear regression with adjustment for age and case status. For those CpGs passing the false discovery rate significance level, we examined the association in a replication set comprised of a non-overlapping group of 187 women from the Sister Study who had DNA methylation data generated using the Infinium HumanMethylation450 BeadChip array. Analysis of this expanded 450K array identified additional BMI-associated sites which were investigated with targeted pyrosequencing. Results Four CpG sites reached genome-wide significance (FDR q<0.05) in the discovery set and associations for all four were significant at strict Bonferroni correction in the replication set. An additional 23 sites passed FDR in the replication set and 5 were replicated by pyrosequencing in the discovery set. Several of the genes identified including ANGPT4, RORC, SOCS3, FSD2, XYLT1, ABCG1, STK39, ASB2, and CRHR2 have been linked to obesity and obesity-related chronic diseases. Conclusions Our findings support the hypothesis that obesity-related epigenetic differences are detectable in blood and may be related to risk of chronic disease.

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“…In 2009, hyper-methylation and repressed SPAK expression levels were found in B cell lymphomas. It was also shown that caspase-dependent apoptosis was impaired when SPAK expression was genetically knocked down, indicating that the loss of SPAK might promote increased cell survival and increased resistance to cancer (14). …”

Section: Physiological Roles Of Spak and Osr1 In Mammalian Systemsmentioning

confidence: 99%

Molecular Physiology of SPAK and OSR1: Two Ste20-Related Protein Kinases Regulating Ion Transport

Gagnon

Delpire

2012

Physiological Reviews

116

108

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SPAK (Ste20-related proline alanine rich kinase) and OSR1 (oxidative stress responsive kinase) are members of the germinal center kinase VI sub-family of the mammalian Ste20 (Sterile20)-related protein kinase family. Although there are 30 enzymes in this protein kinase family, their conservation across the fungi, plant and animal kingdom confirms their evolutionary importance. Already, a large volume of work has accumulated on the tissue distribution, binding partners, signaling cascades, and physiological roles of mammalian SPAK and OSR1 in multiple organ systems. After reviewing this basic information, we will examine newer studies that demonstrate the pathophysiological consequences to SPAK and/or OSR1 disruption, discuss the development and analysis of genetically-engineered mouse models, and address the possible role these serine/threonine kinases might have in cancer proliferation and migration.

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Epigenetic Silencing of Stk39 in B-Cell Lymphoma Inhibits Apoptosis from Genotoxic Stress

Cited by 21 publications

References 40 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

An epigenome-wide study of body mass index and DNA methylation in blood using participants from the Sister Study cohort

Molecular Physiology of SPAK and OSR1: Two Ste20-Related Protein Kinases Regulating Ion Transport

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