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

Talmasov, Daniel; Zhang, Xinjun; Yu, Bing; Nandan, Mandayam O.; Bialkowska, Agnieszka B.; Elkarim, Enas A.; Kuruvilla, Jes; Yang, Vincent W.; Ghaleb, Amr M.

doi:10.1152/ajpgi.00080.2014

Cited by 32 publications

(42 citation statements)

References 64 publications

(86 reference statements)

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“…KLF4 has been shown to act as a radio-protector against apoptotic insults (46). KLF4-deficient cells had decreased levels of the multi-domain Bcl-2 family proteins, Mcl-1 and Bcl-XL (BCL XL ) (47).…”

Section: Discussionmentioning

confidence: 99%

FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis

Natarajan¹,

Stringham

Mohr

et al. 2017

Journal of Lipid Research

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Nonalcoholic steatohepatitis (NASH) patients have elevated plasma saturated free fatty acid levels. These toxic fatty acids can induce liver cell death and our recent results demonstrated that the biliary epithelium may be susceptible to lipotoxicity. Here, we explored the molecular mechanisms of cholangiocyte lipoapoptosis in cell culture and in an animal model of NASH. Treatment of cholangiocytes with palmitate (PA) showed increased caspase 3/7 activity and increased levels of cleaved poly (ADP-ribose) polymerase and cleaved caspase 3, demonstrating cholangiocyte lipoapoptosis. Interestingly, treatment with PA significantly increased the levels of microRNA miR-34a, a pro-apoptotic microRNA known to be elevated in NASH. PA induction of miR-34a was abolished in cholangiocytes transduced with forkhead family of transcription factor class O (FoxO)3 shRNA, demonstrating that FoxO3 activation is upstream of miR-34a and suggesting that FoxO3 is a novel transcriptional regulator of miR-34a. Further, anti-miR-34a protected cholangiocytes from PA-induced lipoapoptosis. Direct and indirect targets of miR-34a, such as SIRT1, receptor tyrosine kinase (MET), Kruppel-like factor 4, fibroblast growth factor receptor (FGFR)1, and FGFR4, were all decreased in PA-treated cholangiocytes. SIRT1 and MET were partially rescued by a miR-34a antagonist. Cholangiocyte apoptosis and miR-34a were dramatically increased in the liver of mice with early histologic features of NASH. Our study provides evidence for the pro-apoptotic role of miR-34a in PA-induced cholangiocyte lipoapoptosis in culture and in the liver.

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Section: Discussionmentioning

confidence: 99%

FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis

Natarajan¹,

Stringham

Mohr

et al. 2017

Journal of Lipid Research

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“…In MEFs it was shown that KLF4 plays an essential role in modulating the DNA damage response and repair mechanisms (34,35). In vivo , KLF4 plays a role as a radio-protective factor against gastrointestinal syndrome in mice following total body γ-irradiation, does so both by inhibiting apoptosis in the acute response to irradiation and by contributing to crypt regeneration (39,41). In this model however, KLF4 is not essential for CDKN1A expression in the intestinal epithelium following total body γ-irradiation.…”

Section: Roles In Diseasesmentioning

confidence: 99%

Krüppel-like factor 4 (KLF4): What we currently know

Ghaleb

Yang

2017

Gene

Self Cite

390

326

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Krüppel-like factor 4 (KLF4) is an evolutionarily conserved zinc finger-containing transcription factor that regulates diverse cellular processes such as cell growth, proliferation, and differentiation. Since its discovery in 1996, KLF4 has been gaining a lot of attention, after it was shown in 2006 as one of four factors required for the induction of pluripotent stem cells (iPSCs). Here we review the current knowledge on the different functions and roles of KLF4 in various tissue and organ systems.

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“…The discovery of KLF4 as one of the four Yamanaka factors (Oct3/4, Sox2, c-Myc, and Klf4) required for stem cell reprogramming (or inducible pluripotent stem cells, iPS) (Park et al, 2008; Takahashi et al, 2007) and its essential role in maintenance of genomic stability (El-Karim et al, 2013) further substantiate its cell fate determinant function. Additionally, functioning as an early response gene, KLF4 is widely involved in host response to inflammation, stress, and injury (Liao et al, 2011; Talmasov et al, 2015), and plays an important role in homeostasis of tissues and/or organs. Thus, KLF4 has drawn extensive attention over recent years.…”

Section: Introductionmentioning

confidence: 99%

KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis

et al. 2016

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SUMMARY Understanding the molecular mechanisms of tumor initiation has significant impact on cancer early detection and intervention. To define the role of KLF4 in pancreatic ductal adenocarcinoma initiation, we used molecular biological analyses and mouse models of klf4 gain- and loss-of-function and mutant Kras. KLF4 is upregulated in and required for acinar-to-ductal metaplasia. Klf4 ablation drastically attenuates the formation of pancreatic intraepithelial neoplasia induced by mutant KrasG12D, whereas upregulation of KLF4 does the opposite. Mutant KRAS and cellular injuries induce KLF4 expression, and ectopic expression of KLF4 in acinar cells reduces acinar lineage- and induces ductal lineage-related marker expression. These results demonstrate that KLF4 induces ductal identity in PanIN initiation and may be a potential target for prevention of PDA initiation.

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

Abstract: AM. Krüppel-like factor 4 is a radioprotective factor for the intestine following ␥-radiation-induced gut injury in mice.

Cited by 32 publications

References 64 publications

FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis

FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis

Krüppel-like factor 4 (KLF4): What we currently know

KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis

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