Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts

Elkarim, Enas A.; Hagos, Engda G.; Ghaleb, Amr M.; Yu, Bing; Yang, Vincent W.

doi:10.1186/1476-4598-12-89

Cited by 47 publications

(56 citation statements)

References 45 publications

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“…Furthermore, results of DNA-damage repair (Fig. 10) strongly support a role for Klf4 in DNA-damage repair response in vivo, consistent with its role in this response that was previously shown in vitro (12,24). Our data suggest a plausible model where, in the absence of Klf4 and following DNA damage, p21 could be driving the cell toward apoptosis and senescence, probably attributable to a defect in the DNA repair mechanism in Klf4 ⌬IS mice, as evident by the ␥H2AX staining.…”

Section: Discussionsupporting

confidence: 68%

Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice

Talmasov

Zhang

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Section: Discussionsupporting

confidence: 68%

Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice

Talmasov

Zhang

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…KLF4 is a member of the KLF family of transcription factors and regulates the proliferation, differentiation, apoptosis, and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancers, such as colorectal cancer (El-Karim et al, 2013). Our analyses also showed that the KLF4 expression level was decreased in LADC.…”

Section: Discussionsupporting

confidence: 66%

Genome-scale meta-analysis of DNA methylation during progression of lung adenocarcinoma

Qh¹,

Xh²,

Zm³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Identification of epigenetic alterations in tumors has become a common method for identifying genes critical to cancer development and progression. Thus, we identified DNA methylation alterations on the genome scale during lung adenocarcinoma (LADC) progression to understand the carcinogenic process and identify clinically relevant biomarkers. We found that epigenetic alterations in LADC mainly occur during the early stage of LADC progression, and there are no significant methylation differences between early-stage and late-stage LADCs. This suggests that DNA methylation alterations characterize a turning point of early events in LADC progression. By comparing DNA methylation between early-stage LADCs and normal lung tissues, we further identified 940 genes with significant alterations in DNA methylation. Sixty-seven genes were found to exhibit strong correlation between methylation alterations and expression changes, based on associated gene expression data. According to gene ontology analysis, these genes are involved in lung development, respiratory 9200-9214 (2015) system development, cell cycle, histidine metabolism, the Wnt signaling pathway, and the p53 signaling pathway. We also found that genes on chromosome 18 most frequently showed promoter hypermethylation. Moreover, we found that LADC-associated DNA hypomethylation occurred preferentially at neither histone H3 lysine 4 nor histone H3 lysine 27 mark domains in human embryonic stem cells (NMDs) and that hypomethylation of NMDs was associated with a poor prognostic signature in LADC. Our findings have important implications for LADC progression because of the identification of novel epigenetic biomarkers potentially involved in early-stage LADC and for establishing the importance of NMD DNA hypomethylation for predicting prognosis in LADC.

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“…Kruppel-like factor 4 (KLF4) is a transcription factor of the KLF family and regulates differentiation, proliferation and apoptosis 36 . KLF4 is a well-known negative transcriptional factor for VSMC contractile proteins, which is reported to be upregulated in VSMC phenotype modulation and plaque instability 8 .…”

Section: Resultsmentioning

confidence: 99%

AMP-Activated Protein Kinase Alpha 2 Deletion Induces VSMC Phenotypic Switching and Reduces Features of Atherosclerotic Plaque Stability

Ding

Zhang

et al. 2016

Circulation Research

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Rationale: AMP-activated protein kinase (AMPK) has been reported to play a protective role in atherosclerosis. However, whether or not AMPKα2 controls atherosclerotic plaque stability remains unknown. Objective: The aim of this study was to evaluate the impact of AMPKα2 deletion on atherosclerotic plaque stability in advanced atherosclerosis at the brachiocephalic arteries (BA) and to elucidate the underlying mechanisms. Methods and Results: Features of atherosclerotic plaque stability and the markers for contractile or synthetic vascular smooth muscle cell (VSMC) phenotypes were monitored in the BA from Apoe−/−AMPKα2−/− mice or VSMC-specific AMPKα2−/− mice in an Apoe−/− background (Apoe−/−AMPKα2sm−/−) fed western diet for 10 weeks. We identified that Apoe−/−AMPKα2−/− mice and Apoe−/−AMPKα2sm−/− mice exhibited similar unstable plaque features, aggravated VSMC phenotypic switching and significant upregulation of Kruppel-like factor 4 (KLF4) in the plaques located in the BA compared to those found in Apoe−/− and Apoe−/−AMPKα2sm+/+ control mice. Pravastatin, an AMPK activator, suppressed VSMC phenotypic switching and alleviated features of atherosclerotic plaque instability in Apoe−/−AMPKα2sm+/+ mice, but not in Apoe−/−AMPKα2sm−/− mice. VSMC isolated from AMPKα2−/− mice displayed a significant reduction of contractile proteins(SM α-actin, calponin and SM-MHC) in parallel with increased detection of synthetic proteins (vimentin and osteopontin) and KLF4, as observed in vivo. KLF4-specific siRNA abolished AMPKα2 deletion-induced VSMC phenotypic switching. Further, pharmacological or genetic inhibition of NF-κB significantly decreased KLF4 upregulation in VSMC from AMPKα2−/− mice. Finally, we found AMPKα2 deletion markedly promoted the binding of NF-κBp65 to KLF4 promoter. Conclusions: This study demonstrated that AMPKα2 deletion induces VSMC phenotypic switching and promotes features of atherosclerotic plaque instability in NF-κB-KLF4 dependent manner.

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Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts

Cited by 47 publications

References 45 publications

Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice

Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice

Genome-scale meta-analysis of DNA methylation during progression of lung adenocarcinoma

AMP-Activated Protein Kinase Alpha 2 Deletion Induces VSMC Phenotypic Switching and Reduces Features of Atherosclerotic Plaque Stability

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