Reduced Phosphorylation of Transcription Factor Elk-1 in Cultured Fibroblasts of a Patient with Premature Aging Syndrome and Insulin Resistance

Knebel, Birgit; Avci, Haluk; Bullmann, Catharina; Kotzka, Jörg; Müller‐Wieland, Dirk

doi:10.1055/s-2004-830554

Cited by 8 publications

(11 citation statements)

References 21 publications

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“…Variant rs2672598 created a binding site for the transcription factor ELK-1, whose activity was reported to be impaired in a patient with a premature form of aging and insulin resistance. 27 We hypothesize, then, that if the risk allele of the promoter SNP rs11200638 results in increased expression of HTRA1, 12,13 then the minor allele of rs2672598 might exert a protective effect by enabling the binding of ELK-1, which could downregulate the expression of HTRA1. On the other hand, the SNP rs2293870 is located in one of the HTRA1 binding domains for IGFs.…”

Section: Discussionmentioning

confidence: 99%

Alleles in the HtrA Serine Peptidase 1 Gene Alter the Risk of Neovascular Age-Related Macular Degeneration

DeAngelis

Adams

et al. 2008

Ophthalmology

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Objective-To examine if the genes encoding the pleckstrin homology domain-containing protein gene (PLEKHA1), hypothetical LOC387715/ARMS2 gene, and HtrA serine peptidase 1 gene (HTRA1) located on the long arm of chromosome 10 (10q26 region) confer risk for neovascular age-related macular degeneration (AMD) in an independent or interactive manner when controlling for complement factor H gene (CFH) genotype and smoking exposure.Design-Retrospective matched-pair case-control study.Participants-Hospital clinic-based sample of 134 unrelated patients with neovascular AMD who have a sibling with normal maculae (268 subjects).Methods-Disease status was ascertained by at least 2 investigators by review of fundus photographs and/or fluorescein angiography according to the Age-Related Eye Disease Study grading scale. If necessary, a home retinal examination was performed (n = 6). A combination of direct sequencing and analysis of 8 highly polymorphic microsatellite markers was used to genotype 33 megabases of the 10q26 region on leukocyte DNA. Smoking history was obtained via a standardized questionnaire and measured in pack-years. The family-based association test, haplotype analysis, multiple conditional logistic regression, and linkage analysis were used to determine significant associations. Main Outcome Measure-Neovascular AMD status.Results-Of the 23 variants we identified in the 10q26 region, 6 were significant. Four of the 6 were novel and included 2 genotypes that reduced risk of AMD. Many single-nucleotide polymorphisms (SNPs), including the previously reported variants rs10490924 (hypothetical NIH Public Access Author ManuscriptOphthalmology. Author manuscript; available in PMC 2014 November 24. Published in final edited form as:Ophthalmology. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptLOC387715/ARMS2) and rs11200638 (HTRA1), defined 2 significant haplotypes associated with increased risk of neovascular AMD. The coding HTRA1 SNP rs2293870, not part of the significant haplotypes containing rs10490924 and rs11200638, showed as strong an association with increased susceptibility to neovascular AMD. Linkage analysis supported our findings of SNP association (P<10 −15 ). No significant interactions were found between any of the SNPs in the 10q26 and smoking or between these SNPs and CFH genotype.Conclusions-Independent of CFH genotype or smoking history, an individual's risk of AMD could be increased or decreased, depending on their genotype or haplotype in the 10q26 region.Neovascular age-related macular degeneration (AMD) is characterized by the growth of abnormal new blood vessels beneath the retina that can cause severe and rapid vision loss due to hemorrhage and exudation. It is this more advanced form that is responsible for the majority of debilitating vision loss due to AMD. In the United States, it is predicted that about 3 million individuals over the age of 50 will have advanced AMD in at least one eye by 2020. 1Current diagnostic methods focus on the detection of ne...

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Section: Discussionmentioning

confidence: 99%

Alleles in the HtrA Serine Peptidase 1 Gene Alter the Risk of Neovascular Age-Related Macular Degeneration

DeAngelis

Adams

et al. 2008

Ophthalmology

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“…Several lines of evidence using this animal model suggest that an altered management of oxidative stress is strongly related to its increased longevity (Hsieh et al 2002;Madsen et al 2004). Supporting evidence for the regulatory effect of Elk-1 is provided in a report by Knebel et al (2005), who found that basal and inducible phosphorylation of Elk-1 was impaired in cultured fibroblasts of a patient with premature aging syndrome and insulin resistance (Knebel et al 2005).…”

Section: Screening For Age-and Cr-related Genesmentioning

confidence: 91%

Revealing system-level correlations between aging and calorie restriction using a mouse transcriptome

Hong

Heo

Kim

et al. 2009

AGE

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Although systems biology is a perfect framework for investigating system-level declines during aging, only a few reports have focused on a comprehensive understanding of system-level changes in the context of aging systems. The present study aimed to understand the most sensitive biological systems affected during aging and to reveal the systems underlying the crosstalk between aging and the ability of calorie restriction (CR) to effectively slow-down aging. We collected and analyzed 478 aging- and 586 CR-related mouse genes. For the given genes, the biological systems that are significantly related to aging and CR were examined according to three aspects. First, a global characterization by Gene Ontology (GO) was performed, where we found that the transcriptome (a set of genes) for both aging and CR were strongly related in the immune response, lipid metabolism, and cell adhesion functions. Second, the transcriptional modularity found in aging and CR was evaluated by identifying possible functional modules, sets of genes that show consistent expression patterns. Our analyses using the given functional modules, revealed systemic interactions among various biological processes, as exemplified by the negative relation shown between lipid metabolism and the immune response at the system level. Third, transcriptional regulatory systems were predicted for both the aging and CR transcriptomes. Here, we suggest a systems biology framework to further understand the most important systems as they age.

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“…Nuclear extracts from fibroblasts of the patient and controls, or HepG2 cells were prepared as described [11]. …”

Section: Methodsmentioning

confidence: 99%

“…MAPK activity assays and western blotting with polyclonal anti-Akt or anti-phospho Akt antibody (New England Biolabs, Frankfurt, Germany) or polyclonal anti-MAPK antibody (BD Transduction; Heidelberg, Germany) were performed as described [11]. …”

Section: Methodsmentioning

confidence: 99%

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A mutation in the c-Fos gene associated with congenital generalized lipodystrophy

Knebel

Kotzka

Hartwig

et al. 2013

Orphanet J Rare Dis

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BackgroundCongenital generalized lipodystrophy (CGL) or Berardinelli–Seip congenital lipodystrophy (BSCL) is a rare genetic syndrome characterized by the absence of adipose tissue. As CGL is thought to be related to malfunctions in adipocyte development, genes involved in the mechanisms of adipocyte biology and maintenance or differentiation of adipocytes, especially transcription factors are candidates. Several genes (BSCL1-4) were found to be associated to the syndrome but not all CGL patients carry mutations in these genes.Methods and resultsIn a patient with CGL and insulin resistance we investigated the known candidate genes but the patient did not carry a relevant mutation. Analyses of the insulin activated signal transduction pathways in isolated fibroblasts of the patient revealed a postreceptor defect altering expression of the immediate early gene c-fos. Sequence analyses revealed a novel homozygous point mutation (c.–439, T→A) in the patients’ c-fos promoter. The point mutation was located upstream of the well characterized promoter elements in a region with no homology to any known cis-elements. The identified mutation was not detected in a total of n=319 non lipodystrophic probands. In vitro analyses revealed that the mutation facilitates the formation of a novel and specific protein/DNA complex. Using mass spectrometry we identified the proteins of this novel complex. Cellular investigations demonstrate that the wild type c-fos promoter can reconstitute the signaling defect in the patient, excluding further upstream signaling alterations, and vice versa the investigations with the c-fos promoter containing the identified mutation generally reduce basal and inducible c-fos transcription activity. As a consequence of the identified point mutation gene expression including c-Fos targeted genes is significantly altered, shown exemplified in cells of the patient.ConclusionThe immediate-early gene c-fos is one essential transcription factor to initiate adipocyte differentiation. According to the role of c-fos in adipocyte differentiation our findings of a mutation that initiates a repression mechanism at c-fos promoter features the hypothesis that diminished c-fos expression might play a role in CGL by interfering with adipocyte development.

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Reduced Phosphorylation of Transcription Factor Elk-1 in Cultured Fibroblasts of a Patient with Premature Aging Syndrome and Insulin Resistance

Cited by 8 publications

References 21 publications

Alleles in the HtrA Serine Peptidase 1 Gene Alter the Risk of Neovascular Age-Related Macular Degeneration

Alleles in the HtrA Serine Peptidase 1 Gene Alter the Risk of Neovascular Age-Related Macular Degeneration

Revealing system-level correlations between aging and calorie restriction using a mouse transcriptome

A mutation in the c-Fos gene associated with congenital generalized lipodystrophy

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