The cerebral cavernous malformation 3 gene is necessary for senescence induction

Aging Cell. 2015 Apr;14(2):274-83. doi: 10.1111/acel.12316. Epub 2015 Feb 5.


Mutations in cerebral cavernous malformation 3 gene are known to result in development of vascular malformations and have recently been proposed to also give rise to meningiomas. We report in this study that lack of CCM3 unexpectedly impairs the senescence response of cells, and this is related to the inability of CCM3-deficient cells to induce the C/EBPβ transcription factor and implement the senescence-associated secretory phenotype. Induction of C/EBPβ and cytokines is also impaired in the absence of CCM3 in response to cytokines in nonsenescent cells, pointing to it being a primary defect and not secondary to impaired senescence. CCM3-deficient cells also have a defect in autophagy at late passages of culture, and this defect is also not dependent on impaired senescence, as it is evident in immortal cells after nutrient starvation. Further, these two defects may be related, as enforcing autophagy in CCM3-deficient late passage cells increases C/EBPβ cytokine expression. These results broaden our knowledge on the mechanisms by which CCM3 deficiency results in disease and open new avenues of research into both CCM3 and senescence biology.

Keywords: CEBPb; PDCD10; SASP; autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / deficiency
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / physiology
  • CCAAT-Enhancer-Binding Protein-beta / biosynthesis
  • Cell Line
  • Cellular Senescence / genetics*
  • Cytokines / biosynthesis
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Endothelial Cells / physiology
  • Humans
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mutation*
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism


  • Apoptosis Regulatory Proteins
  • CCAAT-Enhancer-Binding Protein-beta
  • Cytokines
  • Membrane Proteins
  • PDCD10 protein, human
  • Proto-Oncogene Proteins