Yu, Y. P. & Luo, J. H. Myopodin-mediated suppression of prostate cancer cell migration involves interaction with zyxin. Cancer Res. 66, 7414-7419

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Cancer Research (Impact Factor: 9.33). 09/2006; 66(15):7414-9. DOI: 10.1158/0008-5472.CAN-06-0227
Source: PubMed


Myopodin was identified as a tumor suppressor gene that is frequently deleted in aggressive prostate cancer. Expression of myopodin protein suppresses both tumor growth and metastasis in vitro and in vivo. In the present study employing a yeast two-hybrid system, we found that zyxin, a molecule known to regulate cell motility and migration, binds with myopodin with high affinity. The binding between zyxin and myopodin seems to be direct. Screening of a series of myopodin deletion mutants and peptide competition analyses revealed that myopodin is bound by zyxin at a site located within the sequence of the 19 amino acids at the myopodin COOH terminus. Importantly, this is the same region where the tumor suppressor activity of myopodin is located. The motility and invasion suppression activity of myopodin were significantly weakened in myopodin mutants lacking this sequence. Thus, our studies suggest that zyxin may be a critical functional regulator of myopodin.

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    • "Zyxin was originally purified from avian smooth muscle as a basic phosphoprotein (Beckerle, 1986). Zyxin localizes to focal adhesion plaques as well as adherens junctions, and is implicated in regulating cell adhesion, migration, mechanotransduction and actin-based morphological remodeling in normal and cancerous cells (Drees et al., 1999; Yoshigi et al., 2005; Hoffman et al., 2006; Yu and Luo, 2006; Sy et al., 2006; Colombelli et al., 2009; Mori et al., 2009; Sperry et al., 2010). Zyxin contains an N-terminal proline-rich region and three tandemly arrayed zinc-finger LIM domains at the C-terminus (Sadler et al., 1992). "
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    ABSTRACT: We describe the identification of zyxin as a regulator of synapse maintenance in mechanosensory neurons in C. elegans. zyx-1 mutants lacked PLM mechanosensory synapses as adult animals. However, most PLM synapses initially formed during development but were subsequently lost as the animals developed. Vertebrate zyxin regulates cytoskeletal responses to mechanical stress in culture. Our work provides in vivo evidence in support of such a role for zyxin. In particular, zyx-1 mutant synaptogenesis phenotypes were suppressed by disrupting locomotion of the mutant animals, suggesting that zyx-1 protects mechanosensory synapses from locomotion-induced forces. In cultured cells, zyxin is recruited to focal adhesions and stress fibers via C-terminal LIM domains and modulates cytoskeletal organization via the N-terminal domain. The synapse-stabilizing activity was mediated by a short isoform of ZYX-1 containing only the LIM domains. Consistent with this notion, PLM synaptogenesis was independent of α-actinin and ENA-VASP, both of which bind to the N-terminal domain of zyxin. Our results demonstrate that the LIM domain moiety of zyxin functions autonomously to mediate responses to mechanical stress and provide in vivo evidence for a role of zyxin in neuronal development.
    Preview · Article · Sep 2014 · Development
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    • "This will reduce the co-eluting peptides that would otherwise result in erroneous product ion MS-MS spectra negating the accurate relative quantification efficiency and protein identification accuracy (Fournier et al., 2007). The modulated proteins identified were implicated in the inflammation response (Albini et al., 2007; Albini, Tosetti, Benelli, & Noonan, 2005; DeSouza et al., 2005; Goldstraw, Fitzpatrick, & Kirby, 2007; Nelson, DeMarzo, DeWeese, & Isaacs, 2005), the modulation of the androgen (Cheung-Flynn et al., 2005; De Leon et al., 2011; Hildenbrand et al., 2011; McKeen et al., 2011; Milad et al., 1995; Miyoshi et al., 2003; Nelson et al., 2005; M. H. Yang & Sytkowski, 1998), and prostate cancer metastasis (Ablin, Kynaston, Mason, & Jiang, 2011; Dabbous, Jefferson, Haney, & Thomas, 2011; Di Cristofano et al., 2010; Grisendi, Mecucci, Falini, & Pandolfi, 2006; Hale, Price, Sanchez, Demark-Wahnefried, & Madden, 2001; Jiang & Ablin, 2011; Khanna et al., 2004; C. J. Kim, Sakamoto, Tambe, & Inoue, 2011; Krust, El Khoury, Nondier, Soundaramourty, & Hovanessian, 2011; Moretti et al., 2011; Okuda et al., 2000; Planche et al., 2011; Sun, Song, et al., 2011; Sun, Zhao, et al., 2011; Weng, Ahlen, Astrom, Lui, & Larsson, 2005; Yu & Luo, 2006), as essential hallmark features for these prostate cancer tissue specimens. Another interesting finding that also goes toward validating the accuracy of the proteomic method is the differential expression of several prostate specific cancer markers such as the prostatespecific transglutaminase, the prostate associated gene 4 protein, the prostatic acid phosphatase, and the prostate specific membrane antigen (see Figure 2). "

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    • "PIP5K1C and PXN are necessary for cellular adhesion in a variety of cell types [37], [38]. ZYX is a phosphoprotein which is concentrated at focal adhesions and along the actin cytoskeleton and regulates cellular adhesion and migration [39], [40], [41], [42], [43], [44]. The effect of these and other genes in the two pathways identified which are targeted by miR-886-3p, are consistent with the dramatic effect on cellular proliferation and migration observed in our miR-886-3p functional studies. "
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    ABSTRACT: The molecular basis and characteristics of familial non-medullary thyroid cancer are poorly understood. In this study, we performed microRNA (miRNA) profiling of familial and sporadic papillary thyroid cancer tumor samples. Genome wide miRNA profiling of sporadic and familial papillary thyroid cancer was performed. Differentially expressed miRNAs were validated by quantitative RT-PCR. Ectopic expression of miR-886-3p in thyroid cancer lines was performed to identify pathways targeted by the miRNA, as well as, to determine its effect on tumor cell biology. We found four differentially expressed miRNAs between familial and sporadic papillary thyroid cancer tumor samples. MiR-886-3p and miR-20a were validated to be differentially expressed by 3- and 4-fold, respectively. Pathway analysis of genome-wide expression data on cells overexpressing miR-886-3p and target prediction analysis showed genes involved in DNA replication and focal adhesion pathways were regulated by miR-886-3p. Overexpression of miR-886-3p in thyroid cancer cell lines significantly inhibited cellular proliferation, the number and size of spheroids and cellular migration. Additionally, overexpression of miR-886-3p increased the number of cells in S phase. Our findings for the first time suggest that miR-886-3p plays an important role in thyroid cancer tumor cell biology and regulates genes involved in DNA replication and focal adhesion. Thus, miR-886-3p may play a role in the initiation and or progression of papillary thyroid cancer.
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