ZBP1 enhances cell polarity and reduces chemotaxis

Albert Einstein College of Medicine, New York, New York, United States
Journal of Cell Science (Impact Factor: 5.33). 10/2007; 120(Pt 18):3173-8. DOI: 10.1242/jcs.000638
Source: PubMed

ABSTRACT The interaction of beta-actin mRNA with zipcode-binding protein 1 (ZBP1) is necessary for its localization to the lamellipod of fibroblasts and plays a crucial role in cell polarity and motility. Recently, we have shown that low ZBP1 levels correlate with tumor-cell invasion and metastasis. In order to establish a cause and effect relationship, we expressed ZBP1 in a metastatic rat mammary adenocarcinoma cell line (MTLn3) that has low endogenous ZBP1 levels and delocalized beta-actin mRNA. This leads to localization of beta-actin mRNA, and eventually reduces the chemotactic potential of the cells as well as their ability to move and orient towards vessels in tumors. To determine how ZBP1 leads to these two apparently contradictory aspects of cell behavior--increased cell motility but decreased chemotaxis--we examined cell motility in detail, both in cell culture and in vivo in tumors. We found that ZBP1 expression resulted in tumor cells with a stable polarized phenotype, and reduced their ability to move in response to a gradient in culture. To connect these results on cultured cells to the reduced metastatic ability of these cells, we used multiphoton imaging in vivo to examine tumor cell behavior in primary tumors. We found that ZBP1 expression actually reduced tumor cell motility and chemotaxis, presumably mediating their decreased metastatic potential by reducing their ability to respond to signals necessary for invasion.

Download full-text


Available from: Kyle Lapidus, May 05, 2014
  • Source
    • "It is well established that the translational regulation of localized mRNA has a direct impact on cancer development and metastasis (Rodriguez et al., 2008). For example, the protein levels of the mRNA localization factors ZBP1 and IMP1 directly influence metastasis and tumor progression (Gu et al., 2008, Lapidus et al., 2007, Wang et al., 2004, Kobel et al., 2007, Dimitriadis et al., 2007). LATS/ NDR kinases are implicated in cellular transformation and growth control (Hergovich et al., 2006, Hergovich & Hemmings, 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mechanisms that control mRNA metabolism are critical for cell function, development and stress response. The Saccharomyces cerevisiae mRNA-binding protein Ssd1 has been implicated in mRNA processing, ageing, stress response and maintenance of cell integrity. Ssd1 is a substrate of the LATS/NDR tumour suppressor orthologue Cbk1 kinase. Previous data indicate that Ssd1 localizes to the cytoplasm; however, biochemical interactions suggest that Ssd1 at least transiently localizes to the nucleus. We therefore explored whether nuclear localization is important for Ssd1 cytoplasmic functions. We identified a functional NLS in the N-terminal domain of Ssd1. An Ssd1-derived NLS-GFP fusion protein and several C-terminally truncated Ssd1 proteins, which presumably lack nuclear export sequences, accumulate in the nucleus. Alanine substitution of the Ssd1 NLS prevents Ssd1 nuclear entry, mRNA binding and disrupts Srl1 mRNA localization. Moreover, Ssd1-NLS mutations abolish Ssd1 toxicity in the absence of Cbk1 phosphorylation and cause Ssd1 to localize prominently to cytoplasmic puncta. These data indicate that nuclear shuttling is critical for Ssd1 mRNA binding and Ssd1-mRNA localization in the cytoplasm. Collectively these data support the model that Ssd1 functions analogously to hnRNPs, which bind mRNA co-transcriptionally, are exported to the cytoplasm and target mRNAs to sites of localized translation and P-bodies.
    Molecular Microbiology 08/2011; 81(3):831-49. DOI:10.1111/j.1365-2958.2011.07731.x · 5.03 Impact Factor
  • Source
    • "Cite this article as Cold Spring Harb Perspect Biol 2010;2:a003848 the ZBP1 (Z-DNA-binding protein 1 [Wang et al. 2004; Lapidus et al. 2007]), ROCK (Wyckoff et al. 2006), Mena (Pilippar et al. 2008), cofilin (Wang et al. 2006, 2007b), and EGF receptor (Xue et al. 2006; Kedrin et al. 2009) pathways. The results of these studies confirm that the motility pathways are synergistic to create tumor cells that have passed through epithelialmesenchymal transformation and are capable of chemotaxis to EGF and penetration of basement membrane barriers using invadopodia (reviewed in Oser et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Imaging has become an indispensable tool in the study of cancer biology and in clinical prognosis and treatment. The rapid advances in high resolution fluorescent imaging at single cell level and MR/PET/CT image registration, combined with new molecular probes of cell types and metabolic states, will allow the physical scales imaged by each to be bridged. This holds the promise of translation of basic science insights at the single cell level to clinical application. In this article, we describe the recent advances in imaging at the macro- and micro-scale and how these advances are synergistic with new imaging agents, reporters, and labeling schemes. Examples of new insights derived from the different scales of imaging and relevant probes are discussed in the context of cancer progression and metastasis.
    Cold Spring Harbor perspectives in biology 12/2010; 2(12):a003848. DOI:10.1101/cshperspect.a003848 · 8.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACT ZBP1 (Zipcode Binding Protein 1) is an RNA binding protein involved in many post- transcriptional processes, such as RNA localization, RNA stability and translational control. ZBP1 is abundantly expressed in embryonic development, but its expression is silenced in most adult tissues. Reactivation of the gene has been reported in various human tumors. In this study, we identified a detailed molecular mechanism of ZBP1 transactivation in breast cancer cells. We show that ß-catenin, aprotein that functions in both cell adhesion and transcription, specifically binds to the ZBP1 promoter via a conserved,ß-catenin/TCF4 response element,and activates its gene expression. ZBP1 activation is also closely correlated with nuclear translocation of ß-catenin in human
Show more