Prostate-specific Klf6 Inactivation Impairs Anterior Prostate Branching Morphogenesis through Increased Activation of the Shh Pathway

Leow, Ching Ching; Wang, Bu-Er; Ross, Jed; Chan, Sara M.; Zha, Jiping; Carano, Richard A.D.; Frantz, Gretchen; Shen, Michael M.; Sauvage, Frédéric J. de; Gao, Wei‐Qiang

doi:10.1074/jbc.m109.001776

Cited by 24 publications

(24 citation statements)

References 45 publications

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“…Mice with a floxed KLF6 targeting vector (C57BL/6;129Sv, Genentech, San Francisco, CA [17]) were crossed with mice expressing Cre under control of the albumin promoter (B6.Cg-Tg(Alb-cre)21Mgn/J; Jackson Labs, Bar Harbor, Maine). After further backcrossing, male offspring, expressing Cre with two floxed KLF6 alleles was used as the experimental group, while mice with two floxed alleles and no Cre expression were used as controls as previously described [8, 18].…”

Section: Methodsmentioning

confidence: 99%

Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis

Bechmann

Vetter

Ishida

et al. 2013

Journal of Hepatology

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Background & Aims Dysregulated glucose homeostasis and lipid accumulation characterize non-alcoholic fatty liver disease (NAFLD), but underlying mechanisms are obscure. We report here that Krüppel-like factor 6 (KLF6), a ubiquitous transcription factor that promotes adipocyte differentiation, also provokes the metabolic abnormalities of NAFLD by post-transcriptionally activating PPARα-signaling. Methods Mice with either hepatocyte-specific depletion of KLF6 (‘DeltaHepKlf6’) or global KLF6 heterozygosity (Klf6 +/−) were fed a high fat diet (HFD) or chow for 8 or 16 weeks. Glucose and insulin tolerance tests were performed to assess insulin sensitivity. Overexpression and knockdown of KLF6 in cultured cells enabled the elucidation of underlying mechanisms. In liver samples from a cohort of 28 NAFLD patients, the expression of KLF6-related target genes was quantified. Results Mice with global- or hepatocyte-depletion of KLF6 have reduced body fat content and improved glucose and insulin tolerance, and are protected from HFD-induced steatosis. In hepatocytes, KLF6 deficiency reduces PPARα-regulated genes (Trb3, Pepck) with diminished PPARα-protein but no change in Pparα-mRNA which is explained by the discovery that KLF6 represses miRNA 10b, which leads to induction of PPARα. In NAFLD-patients with advanced disease and inflammation, the expression of miRNA 10b is significantly down-regulated, while PEPCK mRNA is up-regulated; KLF6 mRNA expression also correlates with TRB3 as well as PEPCK gene expression. Conclusions KLF6 increases PPAR -activity, whereas KLF6 loss leads to PPARα repression and attenuation of lipid and glucose abnormalities associated with a high fat diet. The findings establish KLF6 as a novel regulator of hepatic glucose and lipid metabolism in fatty liver.

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Section: Methodsmentioning

confidence: 99%

Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis

Bechmann

Vetter

Ishida

et al. 2013

Journal of Hepatology

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“…Importantly, a number of signaling pathways reported for KLF (dys) regulation of prostate epithelial cell proliferation, differentiation and survival overlap with those elucidated for KLF-mediated uterine function. In particular, KLFs have been reported to participate in androgen receptor-dependent signaling (Liu et al ., 2012; He et al ., 2013), the male counterpart of PGR/ESR signaling in females; in regulating Hedgehog pathway components (Leow et al ., 2009); and in stem cell signaling involving the Notch pathway (Oklem et al ., 2014). However, no KLFs have been demonstrated so far to be indispensable for spermatogenesis.…”

Section: The Next Steps: a Perspectivementioning

confidence: 99%

The Krüppel-like factors in female reproductive system pathologies

Simmen¹,

Heard²,

Simmen³

et al. 2015

Journal of Molecular Endocrinology

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Female reproductive tract pathologies arise largely from dysregulation of estrogen and progesterone receptor signaling leading to aberrant cell proliferation, survival and differentiation. The signaling pathways orchestrated by these nuclear receptors are complex, require the participation of many nuclear proteins serving as key binding partners or targets and involve a range of paracrine and autocrine regulatory circuits. Members of the Krüppel-like family of transcription factors are ubiquitously expressed in reproductive tissues and have been increasingly implicated as critical co-regulators and integrators of steroid hormone actions. Here we explore the involvement of KLF family members in uterine pathology, describe their currently known molecular mechanisms and discuss their potential as targets for therapeutic intervention.

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“…Mouse line expressing lysozyme M promoterdriven Cre recombinase (Lyz2cre) was obtained from The Jackson Laboratory (Bar Harbor, ME). Klf6 floxed (Klf6 fl/fl ) mice were obtained from Genentech (San Francisco, CA) (17). Klf6 floxed mice were crossed with Lyz2cre mice to generate a myeloid-specific deletion of Klf6.…”

Section: Methodsmentioning

confidence: 99%

Kruppel-like Transcription Factor 6 Regulates Inflammatory Macrophage Polarization

Date

Das

Narla

et al. 2014

Journal of Biological Chemistry

137

156

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Background: Macrophage polarization regulates human inflammatory disorders. Results: KLF6 is a novel transcriptional regulator of macrophage polarization. Conclusion: KLF6 regulates macrophage inflammatory gene expression by modulating functions of NF-B and PPAR␥. Significance: Pharmacological agents that modulate KLF6 signaling may allow for therapeutic gain in the treatment of inflammatory disorders.

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Prostate-specific Klf6 Inactivation Impairs Anterior Prostate Branching Morphogenesis through Increased Activation of the Shh Pathway

Cited by 24 publications

References 45 publications

Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis

Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis

The Krüppel-like factors in female reproductive system pathologies

Kruppel-like Transcription Factor 6 Regulates Inflammatory Macrophage Polarization

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