Wnt-induced secreted protein-1 is a prohypertrophic and profibrotic growth factor

Colston, James T.; Rosa, Sam D. de la; Koehler, Melanie; Gonzales, Krista; Mestril, Ruben; Freeman, Gregory L.; Bailey, Steven R.; Chandrasekar, Bysani

doi:10.1152/ajpheart.00428.2007

Cited by 99 publications

(135 citation statements)

References 53 publications

(50 reference statements)

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“…Colston et al (2007) have demonstrated a role for WISP1 in postinfarction cardiac remodeling by demonstrating the proliferative effect of WISP1 on fibroblasts. WIF1 inhibits Wnt signaling by directly binding to Wnt ligands, thus disrupting their ability to bind to the Wnt/frizzled receptor (Van Scoyk et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Genetic variations in the Wnt signaling pathway affect lung function in asthma patients

Sh¹,

Fang²,

Hx³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Identifying genetic determinants for lung function is important in providing insight into the pathophysiology of asthma. The Wnt signal pathway plays a role in lung development and in asthma pathogenesis. However, whether genetic polymorphisms of Wnt signal pathway are associated with lung function in asthma patients remain unclear. We genotyped 2 single nucleotide polymorphisms (SNPs, rs2929973 and rs6581612) involved in the Wnt signal pathway in a cohort of 560 Chinese Han asthmatic children. Associations between each SNP and lung function, in a baseline exam, were tested using multiple linear regression models. We found that rs2929973 of the WISP1 gene was significantly associated with forced expiratory volume in 1 s (FEV1), with the G allele conferring significantly lower FEV1 values. However, the rs6581612 SNP of the WIF1 gene was not associated with differences in FEV1 values. We conclude that genetic variants in Wnt are associated with lung function and suggest that Wnt participates in inflammatory pathways that have an impact on the level of lung function.

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Section: Discussionmentioning

confidence: 99%

Genetic variations in the Wnt signaling pathway affect lung function in asthma patients

Sh¹,

Fang²,

Hx³

et al. 2013

Genet. Mol. Res.

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“…Fifth, increased WISP1 expression has been shown to be causally involved in epithelial cell hyperplasia in breast cancer cell lines (52). Finally, recent evidence has suggested that WISP1 exhibited antiapoptotic and proliferative effects on epithelial as well as mesenchymal cell lines (53,54) and its mRNA expression is associated with lung cancer (55).…”

Section: Figurementioning

confidence: 99%

WNT1-inducible signaling protein–1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis

Königshoff¹,

Kramer²,

Balsara³

et al. 2009

J. Clin. Invest.

361

453

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Idiopathic pulmonary fibrosis (IPF) is characterized by distorted lung architecture and loss of respiratory function. Enhanced (myo)fibroblast activation, ECM deposition, and alveolar epithelial type II (ATII) cell dysfunction contribute to IPF pathogenesis. However, the molecular pathways linking ATII cell dysfunction with the development of fibrosis are poorly understood. Here, we demonstrate, in a mouse model of pulmonary fibrosis, increased proliferation and altered expression of components of the WNT/β-catenin signaling pathway in ATII cells. Further analysis revealed that expression of WNT1-inducible signaling protein-1 (WISP1), which is encoded by a WNT target gene, was increased in ATII cells in both a mouse model of pulmonary fibrosis and patients with IPF. Treatment of mouse primary ATII cells with recombinant WISP1 led to increased proliferation and epithelial-mesenchymal transition (EMT), while treatment of mouse and human lung fibroblasts with recombinant WISP1 enhanced deposition of ECM components. In the mouse model of pulmonary fibrosis, neutralizing mAbs specific for WISP1 reduced the expression of genes characteristic of fibrosis and reversed the expression of genes associated with EMT. More importantly, these changes in gene expression were associated with marked attenuation of lung fibrosis, including decreased collagen deposition and improved lung function and survival. Our study thus identifies WISP1 as a key regulator of ATII cell hyperplasia and plasticity as well as a potential therapeutic target for attenuation of pulmonary fibrosis.

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“…Although multiple cellular pathways may account for the cytoprotective capacity of WISP1 [7,8,10,11,20,21], recent work suggests that mTOR may play a significant role in providing cellular protection with WISP1 [13]. Yet, cellular protection by mTOR may require a level of modulation since high mTOR activity has been associated with apoptotic cell death [43].…”

Section: Discussionmentioning

confidence: 99%

“…WISP1 has been demonstrated to rely upon the phosphorylation and activation of phosphatidylinositol-3-kinase (PI 3-K) and protein kinase B (Akt) [7,8,10,11,20,21] as well as the mammalian target of rapamycin (mTOR) [13] to promote cellular protection. In addition, mTOR phosphorylates and activates p70S6K at threonine 389 and is a marker of mTOR activity [40].…”

Section: Wisp1 Modulates the Post-translational Phosphorylation Of Akmentioning

confidence: 99%

“…WISP1 promotes cytoprotection in multiple cell types through pathways that not only require phosphatidylinositol-3-kinase (PI 3-K) and protein kinase B (Akt) [7,8,10,11,20,21], but also utilize pathways in microglia that involve the mammalian target of rapamycin (mTOR) and the proline rich Akt substrate 40 kDa (PRAS40) [13]. mTOR is the catalytic component of two mTOR complexes termed mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) [22,23].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia

Shang¹,

Chong²,

Wang³

et al. 2012

CNR

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More than 110 million individuals will suffer from cognitive loss worldwide by the year 2050 with a majority of individuals presenting with Alzheimer's disease (AD). Yet, successful treatments for etiologies that involve β-amyloid (Aβ) toxicity in AD remain elusive and await novel avenues for drug development. Here we show that Wnt1 inducible signaling pathway protein 1 (WISP1/ CCN4) controls the post-translational phosphorylation of Akt1, p70S6K, and AMP activated protein kinase (AMPK) to the extent that tuberous sclerosis complex 2 (TSC2) (Ser 1387 ) phosphorylation, a target of AMPK, is decreased and TSC2 (Thr 1462 ) phosphorylation, a target of Akt1, is increased. The ability of WISP1 to limit TSC2 activity allows WISP1 to increase the activity of p70S6K, since gene silencing of TSC2 further enhances WISP1 phosphorylation of p70S6K. However, a minimal level of TSC2 activity is necessary to modulate WISP1 cytoprotection that may require modulation of mTOR activity, since gene knockdown of TSC2 impairs the ability of WISP1 to protect microglia against apoptotic membrane phosphatidylserine (PS) exposure, nuclear DNA degradation, mitochondrial membrane depolarization, and cytochrome c release during Aβ exposure.

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Wnt-induced secreted protein-1 is a prohypertrophic and profibrotic growth factor

Cited by 99 publications

References 53 publications

Genetic variations in the Wnt signaling pathway affect lung function in asthma patients

Genetic variations in the Wnt signaling pathway affect lung function in asthma patients

WNT1-inducible signaling protein–1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis

Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia

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