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Cell Density-Dependent Nuclear Accumulation of ELK3 Is Involved in Suppression of PAI-1 Expression

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Cell Density-Dependent Nuclear Accumulation of ELK3 Is Involved in Suppression of PAI-1 Expression CELL STRUCTURE AND FUNCTION 38: 145–154 (2013) © 2013 by Japan Society for Cell Biology Cell Density-dependent Nuclear Accumulation of ELK3 is Involved in Suppression of PAI-1 Expression Shu Tanaka1, Kazuyuki Nakao1, Toshihiro Sekimoto2, Masahiro Oka1,2, and Yoshihiro Yoneda1,2* 1Department of Frontier Biosciences, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan, 2Department of Biochemistry, Graduate School of Medicine, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan ABSTRACT. Cell-cell contact regulates the proliferation and differentiation of non-transformed cells, e.g., NIH/ 3T3 cells show growth arrest at high cell density. However, only a few reports described the dynamic behavior of transcription factors involved in this process. In this study, we showed that the mRNA levels of plasminogen activator inhibitor type 1 (PAI-1) decreased drastically at high cell density, and that ELK3, a member of the Ets transcription factor family, repressed PAI-1 expression. We also demonstrated that while ELK3 was distributed evenly throughout the cell at low cell density, it accumulated in the nucleus at high cell density, and that binding of DNA by ELK3 at the A domain facilitated its nuclear accumulation. Furthermore, we found that ETS1, a PAI-1 activator, occupied the ELK3-binding site within the PAI-1 promoter at low cell density, while it was released at high cell density. These results suggest that at high cell density, the switching of binding of transcription factors from ETS1 to ELK3 occurs at a specific binding site of the PAI-1 promoter, leading to the cell-density dependent suppression of PAI-1 expression. Key words: High cell density, transcription factors, nucleocytoplasmic transport Introduction (Augustin et al., 1994; Eiraku et al., 2005). In addition, in vivo homeostasis, e.g., tissue formation and control of organ Cell-cell contact plays an essential role in the survival of size, is maintained by cell-cell contact at high cell density non-transformed cells. Several studies have shown that (Zeng and Hong, 2005). Conversely, inappropriate prolifer- fibroblasts, which are typical non-transformed cells, exhibit ative signals usually lead to unregulated and unrestricted growth arrest at high cell density (Levine et al., 1965; Eagle cell proliferation, and may even give rise to transformation and Levine, 1967). For example, at high cell density, NIH/ and tumor progression (Fagotto and Gumbiner, 1996; 3T3 cells, which are mouse embryonic fibroblasts, exhibit Lozano et al., 2003; Kim et al., 2011). However, it is not limited proliferation and migration at high cell density, cou- known how cell-cell contact at high cell density spatially pled with the activation of anti-proliferative signals and regulates anti-proliferative and proliferative signals in cells. subsequent cell cycle arrest at the G0/G1 phases (Holley Plasminogen activator inhibitor type 1 (PAI-1) is a mem- and Kiernan, 1968; Küppers et al., 2010). Vascular endo- ber of the serine protease inhibitor superfamily and is thelial cells, upon contact with neighboring cells, impair involved in fibrinolysis as a secretory protein. PAI-1 inhib- cell proliferation and cell differentiation by the activation of its the functions of urokinase-type plasminogen activator Notch signaling during angiogenesis and embryogenesis and tissue-type plasminogen activator, which convert plasminogen to plasmin, upon binding to their receptors, *To whom correspondence should be addressed: Yoshihiro Yoneda, thereby inhibiting subsequent PAI-1-regulated cell migra- Department of Frontier Biosciences, Graduate School of Frontier Bio- tion by degradation of the extracellular matrix (Strickland, sciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan. 2001; Ploug, 2003; Dellas and Loskutoff, 2005). These Tel: +81–6–6879–4606, Fax: +81–6–6879–4609 E-mail: [email protected] effects are compounded by suppressing the expression of Abbreviations: CRM1, chromosome region maintenance protein 1; DAPI, PAI-1 at the G0 phase, which is re-activated during transi- 4',6-diamidino-2-phenylindole; Ets, E-26 transformation-specific sequence; tion to the G1 phase (Qi et al., 2006). In addition, the EBS, Ets transcription factors binding site; EMSA, electrophoretic mobil- ity shift assay; NES, nuclear export signal; NLS, nuclear localization sig- expression level of PAI-1 has been reported to be associated nal; PAI-1, plasminogen activator inhibitor type 1. with tumor invasion. For example, when malignant keratino- 145 S. Tanaka et al. cytes are transplanted into PAI-1-deficient mice, the cells function antagonistically to regulate PAI-1 expression in a fail to invade the host tissue (Bajou et al., 1998). Further- cell density-dependent manner. Taken together, our findings more, knockdown of PAI-1 by RNA interference represses indicate that high cell density induces the binding of ELK3 the metastasis of human scirrhous gastric cancer cells to EBS, followed by the suppression of PAI-1 expression. (Nishioka et al., 2012). ETS1 and ELK3 are members of Ets transcription factor family. ETS1 is involved in shear stress-induced PAI-1 Results expression, while ELK3 functions as a PAI-1 repressor (Buchwalter et al., 2005; Nakatsuka et al., 2006). It is well PAI-1 mRNA levels at high cell density known that transcription factors have to pass through the nuclear pore complex to function in the nucleus, although To identify genes whose expression levels change in a cell- it remains unclear how the functions of ETS1 and ELK3 density dependent manner, we performed DNA microarray are spatio-temporally regulated in a cell density-dependent analysis using NIH/3T3 cells cultured at low or high cell manner. After translocation into the nucleus, both ETS1 and density. In agreement with a previous report (Comi et al., ELK3 recognize the Ets transcription factor binding site 1995), we found that PAI-1 expression was significantly (EBS), which has the consensus binding core sequence down-regulated at high cell density (Supplemental Table 5'-GGA(A/T)-3' within the promoter region of target genes SII). Northern blotting analysis verified that while PAI-1 (Szymczyna and Arrowsmith, 2000). mRNA levels remained unchanged when the cells were In this study, we characterized the dynamic behavior of cultured at low cell density for over 4 h (Fig. 1A), they transcription factors involved in cell density. We demon- decreased drastically when they were cultured at high cell strated that PAI-1 mRNA levels decreased drastically in density (Fig. 1B). NIH/3T3 cells at high cell density. We also found that Next, to exclude the possibility that factors in extracellu- ELK3 had a role in the suppression of PAI-1 expression at lar fluids may contribute to the decrease in PAI-1 mRNA high cell density and that ELK3 accumulated in the nucleus levels, we incubated NIH/3T3 cells cultured at low cell at high cell density. Further analysis revealed that the density in conditioned medium from cells cultured at low or binding of ELK3 to DNA facilitated its nuclear accumula- high cell density. Whereas there was no difference in PAI-1 tion. Importantly, ETS1 and ELK3 bound to the same EBS mRNA levels when the cells were incubated in conditioned within the PAI-1 promoter, strongly suggesting that they medium from cells at low cell density, incubation in condi- Fig. 1. PAI-1 mRNA levels decrease drastically at high cell density. (A, B) Northern blotting of PAI-1 mRNA levels over 4 h. NIH/3T3 cells were plated at low and high cell density (0 h), and cultured for 4 h, followed by extraction of total RNA every 1 h. PAI-1 mRNA levels over 4 h at high cell density. (C) Conditioned medium was prepared using NIH/3T3 cells that were plated at low and high cell density. Newly prepared cells were then plated at low cell density, and cultured with the conditioned medium for 4 h. (D) NIH/3T3 cells were plated at 60% confluence and treated with 1 μg/mL actinomycin D, an RNA polymerase I inhibitor. Actinomycin D treatment decreased PAI-1 mRNA levels over time, independent of GAPDH. 146 Mechanism of PAI-1 Suppression tioned medium from cells at high cell density resulted in Unlabeled EBS2 dramatically decreased complex forma- only a slight decrease of PAI-1 mRNA levels (Fig. 1C). tion, whereas EBS2mt had no effect (Fig. 2D). Furthermore, These results suggest that although it is possible that extra- when the assay was performed using pGL3-PAI-1(EBSmt), cellular factors affect PAI-1 expression to some extent, which contained the EBS2mt sequence, luciferase activity PAI-1 expression was suppressed in a cell autonomous did not decrease at high cell density. These results indicate manner at high cell density. that EBS2 within the PAI-1 promoter is essential for the Then, to confirm that PAI-1 mRNA levels were regulated optimal binding of proteins, which subsequently facilitates at the transcriptional level, we treated the cells with the the suppression of PAI-1 expression at high cell density. transcriptional inhibitor actinomycin D. Treatment with actinomycin D reduced PAI-1 mRNA levels in a similar Nuclear accumulation of ELK3 and suppression manner as was observed in cells cultured at high cell density of PAI-1 expression at high cell density (Fig. 1D). This finding indicates that high cell density leads to the decrease of PAI-1 mRNA levels mainly at the tran- EBS2 contains a consensus binding site for Ets transcription scriptional level. factors, and it was reported that ELK3, a member of the Ets transcription factor family, functions as a repressor of PAI-1 EBS2 serves as a critical site for the suppression (Buchwalter et al., 2005). To test whether ELK3 is of PAI-1 expression at high cell density involved in the suppression of PAI-1 expression at high cell density, NIH/3T3 cells were transiently transfected with Next, we performed a luciferase assay to identify the pro- pGL3-PAI-1(–190) and pRL-tk in combination with an moter essential for the transcriptional repression of PAI-1 at expression plasmid for ELK3 (pFLAG-ELK3).
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