The Wnt/ -catenin signaling pathway is important in both development and cancer. Casein kinase I (CKI ) is a positive regulator of the canonical Wnt pathway. CKI itself can be regulated in vitro by inhibitory autophosphorylation, and recent data suggest that in vivo kinase activity can be regulated by extracellular stimuli. We show here that the phosphorylation state and kinase activity of CKI ...

Wnt inhibitory factor-1 (WIF-1) acts as a Wnt antagonist and tumor suppressor, but hypermethylation of WIF-1 gene promoter and low expression of WIF-1 activate Wnt signaling aberrantly and induce the development of several human tumors. By using RT-PCR, immunohistochemistry and methylation-specific PCR, we analyzed the expression and methylation of WIF-1 in 4 normal brain tissues, 35 freshly re...

The role of Wnt signaling in hematopoietic stem cell fate decisions remains controversial. We elected to dysregulate Wnt signaling from the perspective of the stem cell niche by expressing the pan Wnt inhibitor, Wnt inhibitory factor 1 (Wif1), specifically in osteoblasts. Here we report that osteoblastic Wif1 overexpression disrupts stem cell quiescence, leading to a loss of self-renewal potent...

Pigment epithelium-derived factor (PEDF) has been shown previously to prevent liver fibrosis and hepatic stellate cell (HSC) activation. By investigating the functional domains in PEDF, we identified a 34-mer peptide (residues Asp44-Asn77) that harbors the same function as the full-length PEDF protein. Not only did the 34-mer suppress the development of fibrosis in carbon tetrachloride (CCl4)-t...

RATIONALE Vascular smooth muscle cell (VSMC) proliferation causes intimal thickening in atherosclerosis and restenosis. Previously, we demonstrated that Wnt/β-catenin signaling upregulates VSMC proliferation in vitro. OBJECTIVE We examined this pathway in vivo and investigated the involvement of specific Wnt proteins in VSMC proliferation. METHODS AND RESULTS Left carotid arteries of TOPgal...

Accumulating lines of evidence have indicated that hyperlipidemia not only is a well-established etiological factor for cardiovascular diseases (CVD), but also plays an active role in regulating bone metabolism. As a mixture of oxidized phospholipids derived from the oxidation of low density lipoprotein (LDL), oxidized 1-palmitoyl2-arachidonoyl-sn-glycero-3-phosphorylcholine (ox-PAPC) is report...

In this issue of Clinical Cancer Research, Naik and colleagues (1) provide the rationale for a synthetic lethal therapy theoretically based on targeted inhibition of vascular endothelial growth factor receptor-1 (VEGFR1)-mediated kinase activity in Wnt/βcatenin-addicted human colorectal cancer (CRC) cells (Fig. 1). Wnt is a cysteine-rich secreted molecule and prototype of a 19-member family of ...

BACKGROUND Wnt signalling dysregulation has been implicated in cancer, including colon and gastric cancer. Initiation of Wnt signalling is modulated by soluble Wnt antagonists (sWAs), including soluble frizzled related proteins, dickkopf (Dkk) proteins, and Wnt inhibitory factor-1 (Wif1). AIMS To evaluate the role of sWAs in upper (gastric) and lower (colon) gastrointestinal tract tumorigenes...

In this issue of Clinical Cancer Research, Naik and colleagues (1) provide the rationale for a synthetic lethal therapy theoretically based on targeted inhibition of vascular endothelial growth factor receptor-1 (VEGFR1)-mediated kinase activity in Wnt/βcatenin-addicted human colorectal cancer (CRC) cells (Fig. 1). Wnt is a cysteine-rich secreted molecule and prototype of a 19-member family of ...

MicroRNAs (miRs) and the canonical Wnt pathway are known to be dysregulated in human cancers and play key roles during cancer initiation and progression. To identify miRs that can modulate the activity of the Wnt pathway we performed a cell-based overexpression screen of 470 miRs in human HEK293 cells. We identified 38 candidate miRs that either activate or repress the canonical Wnt pathway. A ...