851P PLA2G7/PAF-AH as protective factor and potential negative regulator of the Wnt signaling pathway in BRCA1 mutant ovarian cancer

Wnt signaling plays many important roles in animal development. This evolutionarily conserved signaling pathway is highly regulated at all levels. To identify regulators of the Wnt/Wingless (Wg) pathway, we performed a genetic screen in Drosophila. We identified the microRNA miR-8 as an inhibitor of Wg signaling. Expression of miR-8 potently antagonizes Wg signaling in vivo, in part by directly targeting wntless, a gene required for Wg secretion. In addition, miR-8 inhibits the pathway downstream of the Wg signal by repressing TCF protein levels. Another positive regulator of the pathway, CG32767, is also targeted by miR-8. Our data suggest that miR-8 potently antagonizes the Wg pathway at multiple levels, from secretion of the ligand to transcription of target genes. In addition, mammalian homologues of miR-8 promote adipogenesis of marrow stromal cells by inhibiting Wnt signaling. These findings indicate that miR-8 family members play an evolutionarily conserved role in regulating the Wnt signaling pathway.

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Wnt/β-Catenin/Tcf Signaling Induces the Transcription of Axin2, a Negative Regulator of the Signaling Pathway

Molecular and Cellular Biology ◽

10.1128/mcb.22.4.1172-1183.2002 ◽

2002 ◽

Vol 22 (4) ◽

pp. 1172-1183 ◽

Cited By ~ 1080

Author(s):

Eek-hoon Jho ◽

Tong Zhang ◽

Claire Domon ◽

Choun-Ki Joo ◽

Jean-Noel Freund ◽

...

Keyword(s):

Wnt Signaling ◽

Signaling Pathway ◽

Wnt Pathway ◽

Genomic Sequence ◽

Wnt Signaling Pathway ◽

Genomic Region ◽

Negative Regulator ◽

Mobility Shift ◽

Specific Expression

ABSTRACT Axin2/Conductin/Axil and its ortholog Axin are negative regulators of the Wnt signaling pathway, which promote the phosphorylation and degradation of β-catenin. While Axin is expressed ubiquitously, Axin2 mRNA was seen in a restricted pattern during mouse embryogenesis and organogenesis. Because many sites of Axin2 expression overlapped with those of several Wnt genes, we tested whether Axin2 was induced by Wnt signaling. Endogenous Axin2 mRNA and protein expression could be rapidly induced by activation of the Wnt pathway, and Axin2 reporter constructs, containing a 5.6-kb DNA fragment including the promoter and first intron, were also induced. This genomic region contains eight Tcf/LEF consensus binding sites, five of which are located within longer, highly conserved noncoding sequences. The mutation or deletion of these Tcf/LEF sites greatly diminished induction by β-catenin, and mutation of the Tcf/LEF site T2 abolished protein binding in an electrophoretic mobility shift assay. These results strongly suggest that Axin2 is a direct target of the Wnt pathway, mediated through Tcf/LEF factors. The 5.6-kb genomic sequence was sufficient to direct the tissue-specific expression of d2EGFP in transgenic embryos, consistent with a role for the Tcf/LEF sites and surrounding conserved sequences in the in vivo expression pattern of Axin2. Our results suggest that Axin2 participates in a negative feedback loop, which could serve to limit the duration or intensity of a Wnt-initiated signal.

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An Analysis of Polymorphisms Within the Wnt Signaling Pathway in Relation to Ovarian Cancer Risk in a Polish Population

Molecular Diagnosis & Therapy ◽

10.1007/s40291-013-0059-y ◽

2013 ◽

Vol 18 (1) ◽

pp. 85-91 ◽

Cited By ~ 25

Author(s):

Adrianna Mostowska ◽

Piotr Pawlik ◽

Stefan Sajdak ◽

Janina Markowska ◽

Monika Pawałowska ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Risk ◽

Wnt Signaling ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Ovarian Cancer Risk ◽

Polish Population

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Axin, a Negative Regulator of the Wnt Signaling Pathway, Directly Interacts with Adenomatous Polyposis Coli and Regulates the Stabilization of β-Catenin

Journal of Biological Chemistry ◽

10.1074/jbc.273.18.10823 ◽

1998 ◽

Vol 273 (18) ◽

pp. 10823-10826 ◽

Cited By ~ 320

Author(s):

Shosei Kishida ◽

Hideki Yamamoto ◽

Satoshi Ikeda ◽

Michiko Kishida ◽

Ikuo Sakamoto ◽

...

Keyword(s):

Wnt Signaling ◽

Signaling Pathway ◽

Adenomatous Polyposis Coli ◽

Wnt Signaling Pathway ◽

Negative Regulator ◽

Adenomatous Polyposis ◽

Polyposis Coli

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Association between Serum Dickkopf-1 (DKK-1) Glycoprotein and Calcific Deposits on Cardiac Valves and Carotid Intimal-Medial Thickness in Hemodialysis Patients

Cardiorenal Medicine ◽

10.1159/000507183 ◽

2020 ◽

Vol 10 (5) ◽

pp. 313-322

Author(s):

Dalia Younis ◽

Ahmed Bahie ◽

Rasha Elzehery ◽

Ghada El-Kannishy ◽

Ahmed M. Wahab

Keyword(s):

Wnt Signaling ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Significant Negative Correlation ◽

Negative Regulator ◽

Intimal Medial Thickness ◽

Carotid Intimal Medial Thickness ◽

Cardiac Valve Calcification ◽

Calcific Deposits ◽

Score Range

Background: Cardiac valve calcification (CVC) is common in hemodialysis (HD) patients, and associated with cardiovascular and all-cause mortality. Once believed to be a passive process, it is now understood that the Wnt signaling pathway has a major role. The aim of the current study was to assess the relationship between circulating DKK-1, a negative regulator of the Wnt signaling pathway, and CVC, as well as carotid intimal-medial thickness (CIMT) in HD patients. Methods: We enrolled 74 consecutive adults on maintenance HD. Echocardiographic calcification of the mitral valve (MV) and aortic valve (AV) were detected according to Wilkins score (range 0–4), and the study of Tenenbaum et al. [Int J Cardiol. 2004 Mar;94(1):7–13] (range 0–4), respectively. CVC severity was calculated by a supposed score (range 0–8) that represents the sum of calcification grade of MV and AV. CVC severity was classified into absent (CVC score = 0), mild (CVC score = 1–2), moderate (CVC score = 3–4), and severe (CVC score ≥5). Demographic and biochemical data were collected in addition to serum DKK-1 levels and CIMT. Results: CVC was present in 67 patients (91.0%). There was a highly significant negative correlation between serum DKK-1 level and CVC score (r = –0.492; p ≤ 0.001), as well as CIMT (r = –0.611; p ≤ 0.001). Age and CIMT were independent determinants of CVC. Conclusions: CVC is almost present in all HD patients. DKK-1 seems to have a direct relation with CVC and CIMT in HD patients. Age is the strongest independent determinant of CVC.

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A divergent canonical WNT-signaling pathway regulates microtubule dynamics

The Journal of Cell Biology ◽

10.1083/jcb.200309096 ◽

2004 ◽

Vol 164 (2) ◽

pp. 243-253 ◽

Cited By ~ 125

Author(s):

Lorenza Ciani ◽

Olga Krylova ◽

Matthew J. Smalley ◽

Trevor C. Dale ◽

Patricia C. Salinas

Keyword(s):

Wnt Signaling ◽

Signaling Pathway ◽

Transcriptional Activation ◽

Glycogen Synthase ◽

Wnt Signaling Pathway ◽

Negative Regulator ◽

Canonical Wnt Signaling ◽

Microtubule Stability ◽

Gsk 3Β ◽

Canonical Wnt

Dishevelled (DVL) is associated with axonal microtubules and regulates microtubule stability through the inhibition of the serine/threonine kinase, glycogen synthase kinase 3β (GSK-3β). In the canonical WNT pathway, the negative regulator Axin forms a complex with β-catenin and GSK-3β, resulting in β-catenin degradation. Inhibition of GSK-3β by DVL increases β-catenin stability and TCF transcriptional activation. Here, we show that Axin associates with microtubules and unexpectedly stabilizes microtubules through DVL. In turn, DVL stabilizes microtubules by inhibiting GSK-3β through a transcription- and β-catenin–independent pathway. More importantly, axonal microtubules are stabilized after DVL localizes to axons. Increased microtubule stability is correlated with a decrease in GSK-3β–mediated phosphorylation of MAP-1B. We propose a model in which Axin, through DVL, stabilizes microtubules by inhibiting a pool of GSK-3β, resulting in local changes in the phosphorylation of cellular targets. Our data indicate a bifurcation in the so-called canonical WNT-signaling pathway to regulate microtubule stability.

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