Ablation of casein kinase 1 in keratinocytes induces p53-dependent hyperpigmentation of the skin
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 1500
ORGANISM(S): Mus musculus
SUBMITTER: Marco Mernberger
PROVIDER: E-MTAB-5442 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The cross-linked envelope of the mammalian epidermal corneocyte is important as a scaffold for assembly of the lipid barrier of the epidermis. Illustrating its importance, deficient envelope cross-linking by keratinocyte transglutaminase (TGM1) is a major cause of the autosomal recessive congenital ichthyoses, characterized by barrier defects. Expectations that loss of some of the known envelope protein components would also confer an ichthyosis phenotype have been difficult to demonstrate. To help rationalize this observation with one major component, the protein profile of epidermis from loricrin knockout mice has been compared to that of the wild type. Despite the mild phenotype of the knockout, some 40 proteins have been seen to be incorporated into envelope material to significantly different extents. Nearly half of these proteins were also seen to be incorporated to similarly altered extents into the disulfide bonded keratin network of the corneocyte. The results suggest that loss of loricrin alters their incorporation into envelopes as a consequence of protein-protein interactions during cell maturation. Mass spectrometric protein profiling revealed that keratin 1, keratin 10 and loricrin are prominent envelope components and that dozens of other proteins are also components. This finding helps rationalize the potential formation of functional envelopes despite loss of a single component due to availability of many alternative transglutaminase substrates
2016-12-14 | PXD003576 | Pride
Project description:The cross-linked envelope of the mammalian epidermal corneocyte is important as a scaffold for assembly of the lipid barrier of the epidermis. Illustrating its importance, deficient envelope cross-linking by keratinocyte transglutaminase (TGM1) is a major cause of the autosomal recessive congenital ichthyoses, characterized by barrier defects. Expectations that loss of some of the known envelope protein components would also confer an ichthyosis phenotype have been difficult to demonstrate. To help rationalize this observation with one major component, the protein profile of epidermis from loricrin knockout mice has been compared to that of the wild type. Despite the mild phenotype of the knockout, some 40 proteins have been seen to be incorporated into envelope material to significantly different extents. Nearly half of these proteins were also seen to be incorporated to similarly altered extents into the disulfide bonded keratin network of the corneocyte. The results suggest that loss of loricrin alters their incorporation into envelopes as a consequence of protein-protein interactions during cell maturation. Mass spectrometric protein profiling revealed that keratin 1, keratin 10 and filaggrin are prominent envelope components and that dozens of other proteins are minor components. This finding helps rationalize the potential formation of functional envelopes despite loss of a single component due to availability of many alternative transglutaminase substrates.
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Project description:Exercise is a fundamental component of human health that is associated with greater life expectancy and reduced risk of chronic diseases. While the beneficial effects of endurance exercise on human health are well established, the molecular mechanisms responsible for these observations remain unclear. Endurance exercise reduces the accumulation of mitochondrial DNA (mtDNA) mutations, alleviates multisystem pathology, and increases the lifespan of the mtDNA mutator mouse model of aging, in which the proof-reading capacity of mitochondrial polymerase gamma (POLG1) is deficient. Clearly, exercise recruited a POLG1-independent mtDNA repair pathway to induce these adaptations, a novel finding as POLG1 is canonically considered to be the sole mtDNA repair enzyme. Here we investigate the identity of this pathway, and show that endurance exercise prevents mitochondrial oxidative damage, attenuates telomere erosion, and mitigates cellular senescence and apoptosis in mtDNA mutator mice. Unexpectedly, we observe translocation of tumour suppressor protein p53 to mitochondria in response to endurance exercise that facilitates mtDNA mutation repair. Indeed, endurance exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis, preserve mitochondrial morphology, reverse sarcopenia, and mitigate premature mortality in mtDNA mutator mice with muscle-specific deletion of p53. Our data establish an exciting new role for p53 in exercise-mediated maintenance of the mtDNA genome, and presents mitochondrially-targeted p53 as a novel therapeutic modality for aging-associated diseases of mitochondrial etiology. Microarray analysis of gene expression from skeletal muscle (quadriceps femoris) from Mus musculus. N=23 samples per treatment were analysed for whole transcriptiome gene expression profile using NimbleGen Arrays. The treatment groups included wild-type C57Bl/6J mice as the control group, then two treatment groups which both contained homozygous knock-in mtDNA mutator mice (PolG; PolgAD257A/D257A). Once group of these heterozygous knock out mice received regular endurance exercise sessions while the other group remained sedentraty for 6 months. The control group specimens were wild-type litter mates to the transgenic knockout mice.
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