Role of Zyxin in Differential Cell Spreading and Proliferation of Melanoma Cells and Melanocytes

Gaag, Ellen van der; Leccia, Marie‐Thérèse; Dekker, Sybren K.; Jalbert, Nicole L.; Amodeo, Dana M.; Byers, H. Randolph

doi:10.1046/j.0022-202x.2001.01657.x

Cited by 44 publications

(43 citation statements)

References 37 publications

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“…This functional role of endoglin could account for the altered cellular morphology and migration observed in fibroblasts, epithelial, and smooth muscle cells upon endoglin overexpression (6,21,55). In agreement with these findings, overexpression of ZRP-1 leads to decreased cell migration (23); zyxin expression correlates with cell spreading (56), and mislocalization of zyxin produces dramatic cytoskeletal rearrangements that also perturb cell motility (36,38). Most interesting, endoglin-dependent modulation of cell motility appears to be mediated by the presence of zyxin (52).…”

Section: Discussionsupporting

confidence: 76%

Endoglin Regulates Cytoskeletal Organization through Binding to ZRP-1, a Member of the Lim Family of Proteins

Sanz-Rodrı́guez

Guerrero-Esteo

Botella

et al. 2004

Journal of Biological Chemistry

137

119

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Endoglin is a component of the transforming growth factor-␤ receptor complex abundantly expressed at the surface of endothelial cells and plays an important role in cardiovascular development and vascular remodeling. By using the cytoplasmic domain of endoglin as a bait for screening protein interactors, we have identified ZRP-1 (zyxin-related protein 1), a 476-amino acid member that belongs to a family of LIM containing proteins that includes zyxin and lipoma-preferred partner. The endoglin interacting region was mapped within the three double zinc finger LIM domains of the ZRP-1 C terminus. Analysis of the subcellular distribution of ZRP-1 demonstrated that in the absence of endoglin, ZRP-1 mainly localizes to focal adhesion sites, whereas in the presence of endoglin ZRP-1 is found along actin stress fibers. Because the LIM family of proteins has been shown to associate with the actin cytoskeleton, we investigated the possibility of a regulatory role for endoglin with regard to this structure. Expression of endoglin resulted in a dramatic reorganization of the actin cytoskeleton. In the absence of endoglin, F-actin was localized to dense aggregates of bundles, whereas in the presence of endoglin, expressed in endothelial cells, F-actin was in stress fibers and colocalized with ZRP-1. Furthermore, small interfering RNA-mediated suppression of endoglin or ZRP-1, or clustering of endoglin in endothelial cells, led to mislocalization of Factin fibers. These results suggest a regulatory role for endoglin, via its interaction with ZRP-1, in the actin cytoskeletal organization.

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Section: Discussionsupporting

confidence: 76%

Endoglin Regulates Cytoskeletal Organization through Binding to ZRP-1, a Member of the Lim Family of Proteins

Sanz-Rodrı́guez

Guerrero-Esteo

Botella

et al. 2004

Journal of Biological Chemistry

137

119

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“…Overexpression of ZYX has also been demonstrated in melanoma, compared to its biological precursor melanocytes. 12 However, although a relationship between ZYX upregulation and progression of bladder cancer was suggested, 13 our correlative analysis did not demonstrate significant association between messenger RNA levels of ZYX and advanced stage hepatocellular carcinoma tumors. Rather, expression levels of ZYX in patients with multiple tumor lesions were elevated when compared to cases with solitary tumor (B60-fold higher than solitary hepatocellular carcinoma).…”

Section: Discussionmentioning

confidence: 62%

“…Consistent with this observation ZYX expression has been shown to correlate directly with cell proliferation and in decreased the doubling time in melanoma cells. 12 As there was no difference in the apoptotic status of ZYX-deficient, mock and control cells, the effect of ZYX on hepatocellular carcinoma cell growth is unlikely to be mediated by antiapoptotic mechanisms. The ability of ZYX to enhance tumor growth may be attributable to the LIM domains, which have previously been shown to regulate cell proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Novel identification of zyxin upregulations in the motile phenotype of hepatocellular carcinoma

Lai

Pang

et al. 2006

Modern Pathology

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Genome-wide copy number aberrations are common in hepatocellular carcinoma, although the precise genetic events underlying disease progression remain poorly defined. Previous work from our group has indicated several regional chromosomal gains such as chromosome 7q34-q36 that are associated with advanced metastatic tumors. Although the distal chromosome 7q gains have also been implicated in the progression of other malignancies, information on underlying targeted genes is limited. In this study, we have examined the chromosome 7q34-q36 region for involved gene(s) (or genes of interest). An integrated array-based comparative genomic hybridization and transcriptional mapping analyses has enabled us to identify a single candidate, zyxin on chromosome 7q34-q36. This array-derived finding was supported by quantitative reverse transcription-polymerase chain reaction, which also indicated common upregulations of zyxin in hepatocellular carcinoma tumors compared to their corresponding nonmalignant liver tissue (17/52 cases; 33%). Although there was no correlation between zyxin expression and tumor stagings, there was a significant increase in messenger RNA levels in hepatocellular carcinoma cases that presented with multifocal disease (211.57936.9-fold) compared to those with solitary lesions (3.576.3-fold). Moreover, recurrence after resection was common in cases that displayed zyxin overexpressions in the initial resected tumor (P ¼ 0.05). Functional examination of zyxin by small interfering RNA-mediated knockdown in Hep3B cell line indicated a significant inhibition on cell migration through porous membrane (P ¼ 0.002) and invasion through matrigel-coated membrane (P ¼ 0.005). In summary, mapping of chromosome 7q34-q36 has led to the identification of frequent zyxin overexpressions in hepatocellular carcinoma, and a potential role for zyxin in conferring a motile phenotype.

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“…Mislocalisation of zyxin using a peptide inhibitor adversely affects cell spreading and cell migration [Drees et al, 1999] whereas in melanoma cells where zyxin is upregulated, increased cell spreading was seen [Van der Gaag et al, 2002]. TES, like zyxin, has also been shown to interact with mena and VASP proteins [Coutts et al, 2003;Garvalov et al, 2003], and also with ␣-actinin [Garvalov et al, 2003], further supporting the model of TES being part of a complex of proteins at focal adhesions, involved in regulating actin cytoskeleton, cell adhesion, and cell motility.…”

Section: Discussionmentioning

confidence: 92%

Characterisation of chicken TES and its role in cell spreading and motility

Griffith¹,

Coutts²,

Black³

2004

Cell Motil. Cytoskeleton

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Previously we identified TES as a candidate tumour suppressor gene that is located at human chromosome 7q31.1. More recently, we and others have shown TES to encode a novel LIM domain protein that localises to focal adhesions. Here, we present the cloning and functional analysis of the chicken orthologue of TES, cTES. The TES proteins are highly conserved between chicken and human, showing 89% identity at the amino acid level. We show that the cTES protein localised at focal adhesions, actin stress fibres, and sites of cell-cell contact, and GST-cTES can pull-down zyxin and actin. To investigate a functional role for cTES, we looked at the effect of its overexpression on cell spreading and cell motility. Cells overexpressing cTES showed increased cell spreading on fibronectin, and decreased cell motility, compared to RCAS vector transfected control cells. The data from our studies with cTES support our previous findings with human TES and further implicate TES as a member of a complex of proteins that function together to regulate cell adhesion and additionally demonstrate a role for TES in cell motility.

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Role of Zyxin in Differential Cell Spreading and Proliferation of Melanoma Cells and Melanocytes

Cited by 44 publications

References 37 publications

Endoglin Regulates Cytoskeletal Organization through Binding to ZRP-1, a Member of the Lim Family of Proteins

Endoglin Regulates Cytoskeletal Organization through Binding to ZRP-1, a Member of the Lim Family of Proteins

Novel identification of zyxin upregulations in the motile phenotype of hepatocellular carcinoma

Characterisation of chicken TES and its role in cell spreading and motility

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