4.7 Article

Altered MCM Protein Levels and Autophagic Flux in Aged and Systemic Sclerosis Dermal Fibroblasts

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JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 134, 期 9, 页码 2321-2330

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ELSEVIER SCIENCE INC
DOI: 10.1038/jid.2014.69

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资金

  1. Excellence Initiative of the German Federal and State Governments through FRIAS
  2. School of Life Sciences-LifeNet
  3. excellence cluster BIOSS
  4. Deutsche Forschungsgemeinschaft [GZ DE1757/2-1, BR1475/12-1]
  5. Federal Ministry of Education and Research through GerontoSys II-NephAge [031 5896 A]
  6. NIH/NIAMS

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Aging is a common risk factor of many disorders. With age, the level of insoluble extracellular matrix increases leading to increased stiffness of a number of tissues. Matrix accumulation can also be observed in fibrotic disorders, such as systemic sclerosis (SSc). Although the intrinsic aging process in skin is phenotypically distinct from SSc, here we demonstrate similar behavior of aged and SSc skin fibroblasts in culture. We have used quantitative proteomics to characterize the phenotype of dermal fibroblasts from healthy subjects of various ages and from patients with SSc. Our results demonstrate that proteins involved in DNA and RNA processing decrease with age and in SSc, whereas those involved in mitochondrial and other metabolic processes behave the opposite. Specifically, minichrornosome maintenance (MCM) helicase proteins are less abundant with age and SSc, and they exhibit an altered subcellular distribution. We observed that lower levels of MCM7 correlate with reduced cell proliferation, lower autophagic capacity, and higher intracellular protein abundance phenotypes of aged and SSc cells. In addition, we show that SSc fibroblasts exhibit higher levels of senescence compared with their healthy counterparts, suggesting further similarities between the fibrotic disorder and the aging process. Hence, at the molecular level, SSc fibroblasts exhibit intrinsic characteristics of fibroblasts from aged skin.

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