Human Krüppel-like factor 11 inhibits human proinsulin promoter activity in pancreatic beta cells

Niu, Xinjie; Perakakis, Nikolaos; Laubner, Katharina; Limbert, Catarina; Stahl, T.; Brendel, Matthias; Bretzel, R. G.; Seufert, Jochen; Päth, G

doi:10.1007/s00125-007-0667-3

Cited by 20 publications

(10 citation statements)

References 27 publications

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“…Indeed, p.His418Gln resides outside of the R1 domain that serves as a binding site for Sin3A. 10 [13][14][15] our data need to be confirmed by future studies.…”

Section: Discussionmentioning

confidence: 69%

“…KLF11 mutations likely have a wide phenotypic spectrum of diabetes mellitus, similar to that of mutations in HNF1B , INS and KCNJ11 . However, considering that in vitro effects of KLF11 on the INS promoter vary by experimental conditions, our data need to be confirmed by future studies.…”

Section: Discussionmentioning

confidence: 79%

“…Consistent with this, in vitro assays demonstrated that KLF11 binds to GC and CACCC boxes in the promoter of the human insulin gene (INS), and regulates mRNA expression. 8 Interestingly, the regulatory effect of KLF11 on the INS promoter varies according to the cell types and experimental conditions, [13][14][15] suggesting that the function of KLF11 in glucose homeostasis can be modified by other molecules or environmental factors.…”

Section: Introductionmentioning

confidence: 99%

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KLF11 variant in a family clinically diagnosed with early childhood‐onset type 1B diabetes

et al. 2019

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KLF11 is the causative gene for maturity‐onset diabetes of the young 7 (MODY7). KLF11 regulates insulin gene expression through binding to the GC box in the promoter. To date, only two KLF11 mutations have been identified in three families with early‐onset type 2 diabetes. Here, we report a novel KLF11 variant associated with early childhood‐onset type 1B diabetes. The proband and his younger sister exhibited hyperglycemia at age 1 year, and their mother developed diabetes at age 4 years. These three individuals required insulin injection from the initial phase of the disease. Being negative for islet cell autoantibodies, they were diagnosed with type 1B diabetes. Mutation screening for 30 diabetes‐associated genes identified a heterozygous KLF11 variant (p.His418Gln) in the proband and his sister. The variant was also detected in the affected mother, as well as in the allegedly unaffected maternal grandmother. In silico analyses indicated that this variant involves a highly conserved histidine residue in the first C2H2 zinc finger domain which ligates a zinc ion. In vitro analyses showed that expression levels and intracellular localization of His418Gln‐KLF11 were comparable to those of wildtype (WT)‐KLF11. Luciferase assays demonstrated that while WT‐KLF11 suppressed the activity of a 6 × GC box‐containing reporter, His418Gln‐KLF11 lacked the suppressive effect. Notably, His418Gln‐KLF11 canceled the suppressive effect of co‐transfected WT‐KLF11. Such a dominant‐negative effect was absent in the previously reported Ala347Ser‐KLF11 variant. These results indicate that specific variants of KLF11 (MODY7) with a dominant‐negative effect underlie early childhood‐onset type 1B diabetes with incomplete penetrance. This study documents a novel monogenic mutation associated with diabetes in children.

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“…Indeed, p.His418Gln resides outside of the R1 domain that serves as a binding site for Sin3A. 10 [13][14][15] our data need to be confirmed by future studies.…”

Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

KLF11 variant in a family clinically diagnosed with early childhood‐onset type 1B diabetes

et al. 2019

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“…Recently KLF11, a paralog of KLF9, was found to be diminished in uterine fibroids, where it was shown to have a progesterone-dependent, growth suppressive role [22], [23]. KLF11 is also a well-established human disease-associated gene that is etiologically implicated in severe variants of human diabetes, in several cancers as well as in the regulation of diverse endocrine/metabolic pathways [24]–[28]. As uterine endometrium is highly responsive to and regulated by sex steroids, we hypothesized that KLF11 had a role in endometrial biology and disease.…”

Section: Introductionmentioning

confidence: 99%

A Novel Role of the Sp/KLF Transcription Factor KLF11 in Arresting Progression of Endometriosis

et al. 2013

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Endometriosis affects approximately 10% of young, reproductive-aged women. Disease associated pelvic pain; infertility and sexual dysfunction have a significant adverse clinical, social and financial impact. As precise disease etiology has remained elusive, current therapeutic strategies are empiric, unfocused and often unsatisfactory. Lack of a suitable genetic model has impaired further translational research in the field. In this study, we evaluated the role of the Sp/KLF transcription factor KLF11/Klf11 in the pathogenesis of endometriosis. KLF11, a human disease-associated gene is etiologically implicated in diabetes, uterine fibroids and cancer. We found that KLF11 expression was diminished in human endometriosis implants and further investigated its pathogenic role in Klf11-/- knockout mice with surgically induced endometriotic lesions. Lesions in Klf11-/- animals were large and associated with prolific fibrotic adhesions resembling advanced human disease in contrast to wildtype controls. To determine phenotype-specificity, endometriosis was also generated in Klf9-/- animals. Unlike in Klf11-/- mice, lesions in Klf9-/- animals were neither large, nor associated with a significant fibrotic response. KLF11 also bound to specific elements located in the promoter regions of key fibrosis-related genes from the Collagen, MMP and TGF-β families in endometrial stromal cells. KLF11 binding resulted in transcriptional repression of these genes. In summary, we identify a novel pathogenic role for KLF11 in preventing de novo disease-associated fibrosis in endometriosis. Our model validates in vivo the phenotypic consequences of dysregulated Klf11 signaling. Additionally, it provides a robust means not only for further detailed mechanistic investigation but also the ability to test any emergent translational ramifications thereof, so as to expand the scope and capability for treatment of endometriosis.

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“…TGF-β mediates tumor suppression via Smad-dependent signaling, which then regulates the transcription of cell-cycle-associated genes like p15 and p21 [44,61]. But Smad7 also exerts a negative feedback loop by binding to the activated TβR-I, blocking it and preventing phosphorylation [62,63]. Disturbances in the Smad-dependent signaling have recently been shown in human cancers (including pancreatic cancer), and are associated with the ability of tumor cells to escape from the TGF-β-induced growth inhibition [64,65].…”

Section: The Relation Of Klf11 To Cancersmentioning

confidence: 99%

The Distinct Roles of Transcriptional Factor KLF11 in Normal Cell Growth Regulation and Cancer as a Mediator of TGF-β Signaling Pathway

Lin

Mahner

Jeschke

et al. 2020

IJMS

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KLF11 (Krüppel-like factor 11) belongs to the family of Sp1/Krüppel-like zinc finger transcription factors that play important roles in a variety of cell types and tissues. KLF11 was initially described as a transforming growth factor-beta (TGF-β) inducible immediate early gene (TIEG). KLF11 promotes the effects of TGF-β on cell growth control by influencing the TGFβ–Smads signaling pathway and regulating the transcription of genes that induce either apoptosis or cell cycle arrest. In carcinogenesis, KLF11 can show diverse effects. Its function as a tumor suppressor gene can be suppressed by phosphorylation of its binding domains via oncogenic pathways. However, KLF 11 can itself also show tumor-promoting effects and seems to have a crucial role in the epithelial–mesenchymal transition process. Here, we review the current knowledge about the function of KLF11 in cell growth regulation. We focus on its transcriptional regulatory function and its influence on the TGF-β signaling pathway. We further discuss its possible role in mediating crosstalk between various signaling pathways in normal cell growth and in carcinogenesis.

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Human Krüppel-like factor 11 inhibits human proinsulin promoter activity in pancreatic beta cells

Cited by 20 publications

References 27 publications

KLF11 variant in a family clinically diagnosed with early childhood‐onset type 1B diabetes

KLF11 variant in a family clinically diagnosed with early childhood‐onset type 1B diabetes

A Novel Role of the Sp/KLF Transcription Factor KLF11 in Arresting Progression of Endometriosis

The Distinct Roles of Transcriptional Factor KLF11 in Normal Cell Growth Regulation and Cancer as a Mediator of TGF-β Signaling Pathway

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