Wnk1 kinase deficiency lowers blood pressure in mice: A gene-trap screen to identify potential targets for therapeutic intervention

Zambrowicz, Brian; Abuin, Alejandro; Ramirez-Solis, Ramiro; Richter, Lizabeth J.; Piggott, James; BeltrandelRio, Hector; Buxton, Eric C.; Edwards, Joel; Finch, Robert A.; Friddle, Carl; Gupta, Anand P.; Hansen, Gwenn M.; Hu, Yi; Huang, Wenhu; Jaing, Crystal; Key, Billie; Kipp, Peter; Kohlhauff, Buckley; Zhi, Qing; Markesich, Diane C.; Payne, Robert A.; Potter, David; Qian, Ny; Shaw, Joseph R.; Schrick, Jeff; Shi, Zheng Zheng; Sparks, Mary J.; Sligtenhorst, Isaac Van; Vogel, Peter; Walke, Wade; Xu, Nanfei; Zhu, Qingfu; Person, Christophe; Sands, Arthur

doi:10.1073/pnas.2336103100

Cited by 309 publications

(346 citation statements)

References 31 publications

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“…But all these screens are confined to ES cells or their differentiated derivatives and rely on reporter expression. Sequence-driven screens based on the identity of trapped genes [19][20][21][22]30 are intrinsically biased towards highly annotated genes, and limited functional cues can be deduced from the trapped sequences representing ESTs or new genes. With the gene-trap array, virtually any cell type can now be screened for differentially expressed genes.…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of PDGF transcriptional targets by microarray-coupled gene-trap mutagenesis

et al. 2004

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We developed a versatile, high-throughput genetic screening strategy by coupling gene mutagenesis and expression profiling technologies. Using a retroviral gene-trap vector optimized for efficient mutagenesis and cloning, we randomly disrupted genes in mouse embryonic stem (ES) cells and amplified them to construct a cDNA microarray. With this gene-trap array, we show that transcriptional target genes of platelet-derived growth factor (PDGF) can be efficiently and reliably identified in physiologically relevant cells and are immediately accessible to genetic studies to determine their in vivo roles and relative contributions to PDGF-regulated developmental processes. The same platform can be used to search for genes of specific biological relevance in a broad array of experimental settings, providing a fast track from gene identification to functional validation.

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Section: Discussionmentioning

confidence: 99%

Identification and validation of PDGF transcriptional targets by microarray-coupled gene-trap mutagenesis

et al. 2004

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“…This line was developed using the OST324148 OmniBank ES cell line from a sequence tagged gene trap library. 44 Briefly, the gene trap vector included a two expression cassettes (Supplementary Figure S1a). The first cassette encoded for a splice acceptor site (SA), followed by a fusion protein of beta-galactosidase and neomycin, thereby disrupting transcription of the targeted mRNA.…”

Section: Methodsmentioning

confidence: 99%

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

et al. 2014

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Tribbles pseudokinase-3 (TRIB3) has been proposed to act as an inhibitor of AKT although the precise molecular basis of this activity and whether the loss of TRIB3 contributes to cancer initiation and progression remain to be clarified. In this study, by using a wide array of in vitro and in vivo approaches, including a Trib3 knockout mouse, we demonstrate that TRIB3 has a tumorsuppressing role. We also find that the mechanism by which TRIB3 loss enhances tumorigenesis relies on the dysregulation of the phosphorylation of AKT by the mTORC2 complex, which leads to an enhanced phosphorylation of AKT on Ser473 and the subsequent hyperphosphorylation and inactivation of the transcription factor FOXO3. These observations support the notion that loss of TRIB3 is associated with a more aggressive phenotype in various types of tumors by enhancing the activity of the mTORC2/AKT/FOXO axis. Pseudokinases constitute a group of proteins that have a kinase-like domain that lacks at least one of the conserved catalytic residues. 1,2 Different studies have shown that some pseudokinases can exhibit low levels of kinase activity, while others have critical roles as activators of their specific targets. 1,2 Moreover, aberrant regulation of pseudokinases has been implicated in the etiology and progression of a variety of diseases, including cancer. 3 The Tribbles family of pseudokinases was first described in Drosophila as a negative regulator of cell division in early embryogenesis. [4][5][6][7] There are three mammalian Tribbles isoforms (Trib1, Trib2 and Trib3), homologs to the Drosophila tribbles proteins, and they all share a highly conserved central kinase-like domain, which lacks catalytic residues, and a 'tribbles specific' C-terminal domain, which has been proposed to participate in the binding to different Tribbles partners. 8 Tribbles pseudokinase-3 (TRIB3; also named TRB3, NIPK and SKIP3) has been proposed to interact with several proteins, including the transcription factors activating transcription factor 4 (ATF-4) and CHOP 9 as well as with several MAPKs. 10 TRIB3 has also been shown to interact and inhibit AKT, 11 which has been suggested to suppress insulin signaling. 11,12 In addition, administration of different anticancer agents promotes cancer cell death via TRIB3 upregulation and the subsequent inhibition of Akt. [13][14][15][16][17][18][19] However, the precise molecular basis of the regulation of Akt by TRIB3 and whether loss of this pseudokinase may contribute to cancer initiation and progression remains to be clarified.In this study, we investigated the effect of the genetic inactivation of TRIB3 in several cellular and animal models of cancer. Our findings indicate that genetic inhibition of TRIB3 enhances tumorigenesis and that this effect is due -at least primarily -to a selective inactivation of the transcription factor FOXO by the mammalian target of rapamycin complex 2 (mTORC2)/AKT axis. ResultsGenetic inhibition of TRIB3 facilitates oncogene transformation and enhances the tumorigenicity of cancer c...

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“…To date, a direct link between a particular gene impinging histone modifications to BP has not been clearly established. Second, numerous mouse models lacking ENaC and their direct or indirect regulators such as AS, 13 angiotensinogen (Agt), 14 angiotensin-converting enzyme (ACE), 15 MR, 16 Sgk1, 17 WNK1, 18 WNK4, 19 and Period 20 have been reported. However, the role of these models in showing the epigenetic control of BP is still unclear.…”

mentioning

confidence: 99%

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

Chen¹,

H²,

Pochynyuk

et al. 2011

Journal of the American Society of Nephrology

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The putative transcription factor AF17 upregulates the transcription of the epithelial sodium channel (ENaC) genes, but whether AF17 modulates sodium homeostasis and BP is unknown. Here, we generated Af17-deficient mice to determine whether deletion of Af17 leads to sodium wasting and low BP. Compared with wild-type mice, Af17-deficient mice had lower BP (11 mmHg), higher urine volume, and increased sodium excretion despite mildly increased plasma concentrations of aldosterone. Deletion of Af17 led to increased dimethylation of histone H3 K79 and reduced ENaC function. The attenuated function of ENaC resulted from decreased ENaC mRNA and protein expression, fewer active channels, lower open probability, and reduced effective activity. In contrast, inducing high levels of plasma aldosterone by a variety of methods completely compensated for Af17 deficiency with respect to sodium handling and BP. Taken together, these data identify Af17 as a potential locus for the maintenance of sodium and BP homeostasis and suggest that a particular histone modification is directly linked to these processes. Af17-mediated regulation of BP is largely, but not exclusively, the result of modulating ENaC, suggesting it has potential as a therapeutic target for the control of BP.

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Wnk1 kinase deficiency lowers blood pressure in mice: A gene-trap screen to identify potential targets for therapeutic intervention

Cited by 309 publications

References 31 publications

Identification and validation of PDGF transcriptional targets by microarray-coupled gene-trap mutagenesis

Identification and validation of PDGF transcriptional targets by microarray-coupled gene-trap mutagenesis

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

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