Vascular Implications of the Krüppel-Like Family of Transcription Factors

Suzuki, Toru; Aizawa, Kenichi; Matsumura, Takayoshi; Nagai, Ryozo

doi:10.1161/01.atv.0000165656.65359.23

Cited by 111 publications

(93 citation statements)

References 52 publications

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“…Both proteins are members of the same Kru¨ppel-like/Sp family of zinc finger transcription factors. KLFs regulate differentiation and development through their roles in signal transduction, cell proliferation, apoptosis and angiogenesis (Bieker, 2001;Black et al, 2001;Suzuki et al, 2005). KLF6 is ubiquitously expressed and contains a highly conserved COOH terminus zinc finger DNAbinding domain that interacts with GC box motifs in target promoters, often containing no or only weak TATA-boxes (Turner and Crossley, 1999).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 2008

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“…There is increasing evidence to suggest that KLFs play a central role in the regulation of cell growth, proliferation, differentiation and tumorigenesis. KLF5 is the fifth member of this family, and has been demonstrated to mediate various aspects of cardiovascular physiology, including remodeling, differentiation and development (Shi et al, 1999;Nagai et al, 2003;Ghaleb et al, 2005;Suzuki et al, 2005). Recent studies also suggest that KLF5 plays a role in tumor progression in breast and prostate cancers (Chen et al, 2002(Chen et al, , 2003.…”

Section: Introductionmentioning

confidence: 99%

Kruppel-like factor 5 modulates p53-independent apoptosis through Pim1 survival kinase in cancer cells

Zhao

et al. 2007

Oncogene

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Although Kruppel-like factor 5 (KLF5) is a transcription factor that has been implicated in pathways critical to carcinogenesis, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Here, we describe a novel role for KLF5 in a p53-independent apoptotic pathway. Using RNA-interference technology, we show that cells deficient in KLF5 have increased sensitivity to DNA damage, regardless of p53 status. Both p53 and p53-dependent factors are unaffected by KLF5 depletion. Instead, the apoptotic phenotype consequent to damage is associated with reduced bad phosphorylation, and downregulation of Pim1. Consistently, transfection of wild-type Pim1 is sufficient to rescue this phenotype. Previous data have shown a number of putative Sp1-binding consensus sequences on the Pim1 promoter. Remarkably, chromatin immunoprecipitation studies show that KLF5 binds to the Pim1 promoter, and that binding increases soon after damage. These results identify a novel, p53-independent apoptotic pathway through which KLF5 functions in response to DNA damage. Therapeutic deregulation of this pathway could be used to modulate chemosensitivity.

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“…23b). Finally, we tested whether other KLF family members, including KLF2 and KLF5, may contribute to Twist1-Jagged1-induced endothelial differentiation 17 . However, quantitative real-time PCR analysis showed that knockdown of Jagged1 in Twist1-overexpressing OECM1 cells did not decrease the KLF2 or KLF5 mRNA levels ( Supplementary Fig.…”

Section: Oecm1-twist1mentioning

confidence: 99%

“…KLF4 is a core component of the pluripotency transcription network that has been used to reprogram somatic cells into induced pluripotent stem cells 16 . KLF4 regulates endothelial barrier and is implicated in vasculogenesis 17,18 . Recent evidence has shown that pluripotency factors regulate endoderm specification 19 .…”

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confidence: 99%

Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis

et al. 2014

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The mechanisms controlling tumour-induced angiogenesis are presently not clear. In principle, angiogenesis can be achieved through the activation of endothelial cells in existing vessels or by transdifferentiation of tumour cells into endothelial cells. However, whether tumour cells can go through a prior epithelial-mesenchymal transition and further differentiate into endothelial cells remains unknown. Here we show that overexpression of Twist1, a transcriptional regulator that induces and promotes cancer metastasis, leads to endothelial differentiation in head and neck cancer (HNC) cells. Induction of Jagged1 expression by Twist1 is essential for Twist1-induced endothelial differentiation. The Jagged1/ Notch signalling subsequently activates KLF4, inducing stem-like properties in HNC cells and conferring them with drug resistance. Our results indicate that the Twist1-Jagged1/KLF4 axis is essential both for transdifferentiation of tumour cells into endothelial cells and for chemoresistance acquisition.

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Vascular Implications of the Krüppel-Like Family of Transcription Factors

Abstract: Abstract-The

Cited by 111 publications

References 52 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

Kruppel-like factor 5 modulates p53-independent apoptosis through Pim1 survival kinase in cancer cells

Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis

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