The LIM-homeodomain transcription factor LMX1B regulates expression of NF-kappa B target genes

Rascle, Anne; Neumann, Tanja; Raschta, Anne-Sarah; Neumann, Astrid; Heining, Eva; Kastner, Juergen; Witzgall, Ralph

doi:10.1016/j.yexcr.2008.10.012

Cited by 24 publications

(35 citation statements)

References 82 publications

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“…Knock-down of IL-33 using siRNA in other transcription factors such as NF-B [46] to increase target specificity and also play a key role in innate immunity [47]. A role for both innate and adaptive immune systems has been proposed in the development of PAH [48].…”

Section: Regulation Of Gene Expression By Il-33mentioning

confidence: 99%

Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension

Shao

Perros

Caramori

et al. 2014

Biochemical and Biophysical Research Communications

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Section: Regulation Of Gene Expression By Il-33mentioning

confidence: 99%

Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension

Shao

Perros

Caramori

et al. 2014

Biochemical and Biophysical Research Communications

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“…[11][12][13]36,37 To show that the genetic changes observed in the inducible Lmx1b knockout mice were lox/lox ; NPHS2:rtTA mice were administered 2 mg/ml doxycycline in the drinking water over a period of 7 days. (A) Glomeruli were isolated and cultured for 4 days to allow for the outgrowth of podocytes.…”

Section: Evidence For the Regulation Of The Actin Cytoskeleton By Lmx1bmentioning

confidence: 99%

LMX1B is Essential for the Maintenance of Differentiated Podocytes in Adult Kidneys

Burghardt

Kastner

Suleiman

et al. 2013

Journal of the American Society of Nephrology

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Mutations of the LMX1B gene cause nail-patella syndrome, a rare autosomal-dominant disorder affecting the development of the limbs, eyes, brain, and kidneys. The characterization of conventional Lmx1b knockout mice has shown that LMX1B regulates the development of podocyte foot processes and slit diaphragms, but studies using podocyte-specific Lmx1b knockout mice have yielded conflicting results regarding the importance of LMX1B for maintaining podocyte structures. In order to address this question, we generated inducible podocyte-specific Lmx1b knockout mice. One week of Lmx1b inactivation in adult mice resulted in proteinuria with only minimal foot process effacement. Notably, expression levels of slit diaphragm and basement membrane proteins remained stable at this time point, and basement membrane charge properties also did not change, suggesting that alternative mechanisms mediate the development of proteinuria in these mice. Cell biological and biophysical experiments with primary podocytes isolated after 1 week of Lmx1b inactivation indicated dysregulation of actin cytoskeleton organization, and time-resolved DNA microarray analysis identified the genes encoding actin cytoskeleton-associated proteins, including Abra and Arl4c, as putative LMX1B targets. Chromatin immunoprecipitation experiments in conditionally immortalized human podocytes and gel shift assays showed that LMX1B recognizes AT-rich binding sites (FLAT elements) in the promoter regions of ABRA and ARL4C, and knockdown experiments in zebrafish support a model in which LMX1B and ABRA act in a common pathway during pronephros development. Our report establishes the importance of LMX1B in fully differentiated podocytes and argues that LMX1B is essential for the maintenance of an appropriately structured actin cytoskeleton in podocytes.

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“…In the caspase-3/7 screen 30 'hits' had z scores >2 (see ESM Table 2) and were subjected to validation. Of those, 16 (listed in Table 1) were found to be highly validated itself, as well as siRNAs to Tia1 (which encodes an apoptosis-promoting factor) [19], Pou4f2 (which enhances the pro-apoptotic effects of p53) [20] and Lmx1b [21], which regulates the expression of NF-κB target genes, a key element in the induction of beta cell apoptosis [22]. Similarly, Atg4b [23] scored high in the CTB screen.…”

Section: Resultsmentioning

confidence: 99%

“…A number of genes shown in our screens to be pro-apoptotic are established players in cytokine-induced death. These include IRF7 [32], CEBPB and LMX1B, the last two of which are encoding inducers of NF-κΒ, a mediator of cytokine-triggered beta cell death [21,33].…”

Section: Discussionmentioning

confidence: 99%

An siRNA screen identifies transmembrane 7 superfamily member 3 (TM7SF3), a seven transmembrane orphan receptor, as an inhibitor of cytokine-induced death of pancreatic beta cells

et al. 2011

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Aims/hypothesis Pro-inflammatory cytokines induce death of pancreatic beta cells, leading to the development of type 1 diabetes. We sought to identify novel players and the underlying mechanisms involved in this process. Methods A high-throughput screen of 3,850 mouse small interfering RNAs (siRNAs) was performed in cytokinetreated MIN6 beta cells. Cells were transfected with the different siRNAs and then treated with a combination of TNFα, IL-1β and IFNγ. Cellular apoptosis (caspase-3/7 activity), and changes in cellular reducing power and cell morphology were monitored. The resulting data were analysed and the corresponding z scores calculated. Results Several gene families were identified as promoting cytokine-induced beta cell apoptosis, the most prominent being those encoding ubiquitin ligases and serine/threonine kinases. Conversely, deubiquitinating enzymes appeared to reduce apoptosis, while protein phosphatases were mainly associated with lowering cellular reducing power. The screen suggested with high confidence the involvement of several novel genes in cytokine-induced beta cell death, including Camkk2, Epn3, Foxp3 and Tm7sf3, which encodes an orphan seven transmembrane receptor. siRNAs to Tm7sf3 promoted cytokine-induced death of MIN6 cells and human pancreatic islets, and abrogated insulin secretion in these cells. These findings implicate transmembrane 7 superfamily member 3 as a potential new player in the inhibition of cytokine-induced death and in the promotion of insulin secretion from pancreatic beta cells. Conclusions/interpretation The signalling pathways and novel genes that we identified in this screen and that mediate beta cell death offer new possible targets for therapeutic intervention in diabetes and its adverse complications.

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The LIM-homeodomain transcription factor LMX1B regulates expression of NF-kappa B target genes

Cited by 24 publications

References 82 publications

Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension

Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension

LMX1B is Essential for the Maintenance of Differentiated Podocytes in Adult Kidneys

An siRNA screen identifies transmembrane 7 superfamily member 3 (TM7SF3), a seven transmembrane orphan receptor, as an inhibitor of cytokine-induced death of pancreatic beta cells

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