The cerebral cavernous malformation 3 gene is necessary for senescence induction.

Ana Guerrero,Selina Raguz,Jesús Gil,Cristina Iglesias,Celia M Pombo,Ebel Floridia,Juan Zalvide

doi:10.1111/acel.12316

Ana Guerrero, Selina Raguz + Show 5 more

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https://doi.org/10.1111/acel.12316

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Abstract

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.

Highlights

Cellular senescence develops in response to a variety of stresses, including telomere attrition, unscheduled DNA replication, oxidative stress, suboptimal culture conditions, or the presence of an activated oncogene (Hayflick, 1965; Kuilman et al, 2010)
In the last few years, several other physiological changes have been shown to be important for the full implementation of the senescence program; among these are the secretion of a plethora of extracellular messengers, most prominently cytokines, by senescent cells (Krtolica et al, 2001; Coppe et al, 2006; Acosta et al, 2008; Kuilman et al, 2008; Kuilman & Peeper, 2009), and the stimulation of the process of macroautophagy (Kurz et al, 2000; Young et al, 2009; Narita et al, 2011)
Autophagy is necessary in this context for the efficient synthesis and secretion of extracellular messengers (Young et al, 2009), and once established, the synthesis and secretion of cytokines can be self-sustained by a positive feedback loop involving the transcription factors NFjB and C/EBPb (Acosta et al, 2008)

Summary

Introduction

Cellular senescence develops in response to a variety of stresses, including telomere attrition, unscheduled DNA replication, oxidative stress, suboptimal culture conditions, or the presence of an activated oncogene (in the latter case being called oncogene-induced senescence, OIS) (Hayflick, 1965; Kuilman et al, 2010). It was first described in cells in culture and is widely accepted as an important antioncogenic mechanism in vivo (Braig et al, 2005; Collado et al, 2005; Michaloglou et al, 2005). Several functions have been proposed for CCM3, including modulation of cell death, especially after oxidative stress (Chen et al, 2009; Schleider et al, 2010; Fidalgo et al, 2012; Zhang et al, 2012), regulation of transmembrane signaling and cell growth (Ma et al, 2007; Kleaveland et al, 2009; He et al, 2010; Lin et al, 2010), and playing a role in membrane trafficking, Golgi apparatus biogenesis, cell migration, and regulated secretion (Fidalgo et al, 2010; Zhang et al, 2013; Louvi et al, 2014)

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