The cerebral cavernous malformation 3 gene is necessary for senescence induction

Summary 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 CCM 3 unexpectedly impairs the senescence response of cells, and this is related to the inability of CCM 3‐deficient cells to induce the C/ EBP β transcription factor and implement the senescence‐associated secretory phenotype. Induction of C/ EBP β and cytokines is also impaired in the absence of CCM 3 in response to cytokines in nonsenescent cells, pointing to it being a primary defect and not secondary to impaired senescence. CCM 3‐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 CCM 3‐deficient late passage cells increases C/ EBP β cytokine expression. These results broaden our knowledge on the mechanisms by which CCM 3 deficiency results in disease and open new avenues of research into both CCM 3 and senescence biology.