Transcriptional activation of endoglin and transforming growth factor-β signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury

Botella, Luisa María; Sánchez-Elsner, Tilman; Sanz-Rodrı́guez, Francisco; Kojima, Soichi; Shimada, Jun; Guerrero-Esteo, Mercedes; Cooreman, Michael P.; Ratziu, Vlad; Langa, Carmen; Vary, Calvin P.H.; Ramírez, José Ramón; Friedman, Scott L.; Bernabéu, Carmelo

doi:10.1182/blood.v100.12.4001

Cited by 168 publications

(188 citation statements)

References 58 publications

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“…Regarding KLF6-mediated, Sp1-dependent activation of DAPK2, our data are in line with earlier reports showing physical interaction of SP1 and KLF6/Zf9 in activation of transforming growth factor-b and endoglin (Kim et al, 1998;Botella et al, 2002). Although KLF6 and Sp1 have highly similar DNA recognition sites, both may be present at GC-rich promoters, stabilizing each other, recruiting additional factors and thus building a transcriptional network enabling the cell to respond flexibly to various signals.…”

Section: Dapk2 Is Regulated By E2f1 and Klf6supporting

confidence: 91%

“…On the other hand, E2F1 is an Sp1 binding partner and its cell-cycle regulated association with Sp1 has been proposed to be important for fine tuning the transcription of respective target genes (Karlseder et al, 1996;Lin et al, 1996). Similarly, Sp1 interaction with its close relative KLF6 is essential for activation of GC-rich promoters (Kim et al, 1998;Botella et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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DAPK2 is a novel E2F1/KLF6 target gene involved in their proapoptotic function

et al. 2008

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Death-associated protein kinase 2 (DAPK2) belongs to a family of proapoptotic Ca 2 þ /calmodulin-regulated serine/ threonine kinases. We recently identified DAPK2 as an enhancing factor during granulocytic differentiation. To identify transcriptional DAPK2 regulators, we cloned 2.7 kb of the 5 0 -flanking region of the DAPK2 gene. We found that E2F1 and Kru¨ppel-like factor 6 (KLF6) strongly activate the DAPK2 promoter. We mapped the E2F1 and KLF6 responsive elements to a GC-rich region 5 0 of exon 1 containing several binding sites for KLF6 and Sp1 but not for E2F. Moreover, we showed that transcriptional activation of DAPK2 by E2F1 and KLF6 is dependent on Sp1 using Sp1/KLF6-deficient insect cells, mithramycin A treatment to block Sp1-binding or Sp1 knockdown cells. Chromatin immunoprecipitation revealed recruitment of Sp1 and to lesser extent that of E2F1 and KLF6 to the DAPK2 promoter. Activation of E2F1 in osteosarcoma cells led to an increase of endogenous DAPK2 paralleled by cell death. Inhibition of DAPK2 expression resulted in significantly reduced cell death upon E2F1 activation. Similarly, KLF6 expression in H1299 cells increased DAPK2 levels accompanied by cell death that is markedly decreased upon DAPK2 knockdown. Moreover, E2F1 and KLF6 show cooperation in activating the DAPK2 promoter. In summary, our findings establish DAPK2 as a novel Sp1-dependent target gene for E2F1 and KLF6 in cell death response.

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Section: Dapk2 Is Regulated By E2f1 and Klf6supporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

DAPK2 is a novel E2F1/KLF6 target gene involved in their proapoptotic function

et al. 2008

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“…For example, GKLF (KLF4) activates p21(WAF1/Cip1) through a specific Sp1-like cis-element in the p21(WAF1/Cip1) proximal promoter and can form a complex with the tumor suppressor p53 (Zhang et al, 2000). KLF6 transactivates the promoters of collagen a1(I) (Ratziu et al, 1998), urokinase type plasminogen activator (Kojima et al, 2000), TGF-b1, TGF-b1 receptors, and endoglin (Botella et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6

Kimmelman

Narla

et al. 2004

Oncogene

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“…Our results further establish p21 as a transcriptional target of KLF6. In addition to a direct antiproliferative effect mediated by p21, KLF6 may also indirectly inhibit cell growth through its ability to upregulate the antiproliferative cytokine transforming growth factor (TGF)b1 and its receptors (Kim et al, 1998) and to stimulate plasmin mediated activation of latent TGFb1 by driving transcription of the urokinase-type plasminogen activator gene (Botella et al, 2002).The decrease in hepatic synthetic function in KLF6 TG mice may reflect an indirect effect of impaired cellular growth, similar to that observed in TG mice with hepatocyte-specific expression of p21 (Wu et al, 1996). Alternatively, KLF6 might directly impair hepatocyte differentiation through transactivation of target genes not yet identified.…”

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confidence: 99%

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confidence: 99%

In vivo regulation of p21 by the Kruppel-like factor 6 tumor-suppressor gene in mouse liver and human hepatocellular carcinoma

et al. 2007

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Kruppel-like factor (KLF) 6 is a tumor-suppressor gene functionally inactivated by loss of heterozygosity, somatic mutation and/or alternative splicing that generates a dominant-negative splice form, KLF6-SV1. Wild-type KLF6 (wtKLF6) expression is decreased in many human malignancies, which correlates with reduced patient survival. Additionally, loss of the KLF6 locus in the absence of somatic mutation in the remaining allele occurs in a number of human cancers, raising the possibility that haploinsufficiency of the KLF6 gene alone contributes to cellular growth dysregulation and tumorigenesis. Our earlier studies identified the cyclin-dependent kinase inhibitor p21 as a transcriptional target of the KLF6 gene in cultured cells, but not in vivo. To address this issue, we have generated two genetic mouse models to define the in vivo role of KLF6 in regulating cell proliferation and p21 expression. Transgenic overexpression of KLF6 in the liver resulted in a runted phenotype with decreased body and liver size, with evidence of decreased hepatocyte proliferation, increased p21 and reduced proliferating cell nuclear antigen expression. In contrast, mice with targeted deletion of one KLF6 allele (KLF6 þ /À) display increased liver mass with reduced p21 expression, compared to wild type littermates. Moreover, in primary hepatocellular carcinoma samples, there is a significant correlation between wtKLF6 and p21 mRNA expression. Combined, these data suggest that haploinsufficiency of the KLF6 gene may regulate cellular proliferation in vivo through decreased transcriptional activation of the cyclin-dependent kinase inhibitor p21. Oncogene (2007) 26, 4428-4434; doi:10.1038/sj.onc.1210223; published online 5 February 2007 Keywords: KLF6; Kruppel-like factor; tumor-suppressor gene; p21; haploinsufficiency Kruppel-like factor 6 (KLF6) belongs to the Kruppellike family of transcription factors, which play roles in the regulation of diverse cellular processes including development, differentiation, proliferation and apoptosis (Bieker, 2001). Functional inactivation of the KLF6 gene occurs through several mechanisms, including loss of heterozygosity (LOH), somatic mutation and/or increased alternative splicing that yields a dominantnegative splice isoform, KLF6-SV1. KLF6 dysregulation has been demonstrated in a number of human cancers including prostate (Narla et al., 2001;Chen et al., 2003), colorectal , non-smallcell lung (Ito et al., 2004), gastric (Cho et al., 2005), nasopharyngeal (Chen et al., 2002), hepatocellular (Kremer-Tal et al., 2004) and ovarian carcinomas (DiFeo et al., 2006b) as well as glioma (Jeng et al., 2003). Furthermore, decreased KLF6 mRNA expression is associated with reduced patient survival in prostate (Singh et al., 2002;Glinsky et al., 2004) and lung cancers (Kettunen et al., 2004). Interestingly, reconstitution of KLF6 decreases cell proliferation and reverts tumorigenicity in glioblastoma cell lines (Kimmelman et al., 2004).Depending on the cell type and context, KLF6's growth-suppressive prop...

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Transcriptional activation of endoglin and transforming growth factor-β signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury

Cited by 168 publications

References 58 publications

DAPK2 is a novel E2F1/KLF6 target gene involved in their proapoptotic function

DAPK2 is a novel E2F1/KLF6 target gene involved in their proapoptotic function

Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6

In vivo regulation of p21 by the Kruppel-like factor 6 tumor-suppressor gene in mouse liver and human hepatocellular carcinoma

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