The cerebral cavernous malformation 3 gene is necessary for senescence induction

Abstract

Mutations in cerebral cavernous malformation 3 gene are knownto result in development of vascular malformations and haverecently been proposed to also give rise to meningiomas. Wereport in this study that lack of CCM3 unexpectedly impairs thesenescence response of cells, and this is related to the inability ofCCM3-deficient cells to induce the C/EBPb transcription factor andimplement the senescence-associated secretory phenotype.Induction of C/EBPb and cytokines is also impaired in the absenceof CCM3 in response to cytokines in nonsenescent cells, pointingto it being a primary defect and not secondary to impairedsenescence. CCM3-deficient cells also have a defect in autophagyat late passages of culture, and this defect is also not dependenton impaired senescence, as it is evident in immortal cells afternutrient starvation. Further, these two defects may be related, asenforcing autophagy in CCM3-deficient late passage cellsincreases C/EBPb cytokine expression. These results broaden ourknowledge on the mechanisms by which CCM3 deficiency resultsin disease and open new avenues of research into both CCM3 andsenescence biology