This Article Full Text Full Text (PDF) All Versions of this Article: 40/4/1474    most recent STROKEAHA.108.527135v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chen, L. Articles by Gunel, M. Search for Related Content PubMed PubMed Citation Articles by Chen, L. Articles by Gunel, M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Genetics Home Reference Related Collections Apoptosis Cerebral Aneurysm, AVM, & Subarachnoid hemorrhage

(Stroke. 2009;40:1474.)
© 2009 American Heart Association, Inc.

Original Contributions

Apoptotic Functions of PDCD10/CCM3, the Gene Mutated in Cerebral Cavernous Malformation 3

Leiling Chen, MD; Gamze Tanriover, MSc; Hiroko Yano, PhD; Robert Friedlander, MD; Angeliki Louvi, PhD Murat Gunel, MD

From the Departments of Neurosurgery and Neurobiology and the Yale Program on Neurogenetics (L.C., G.T., A.L., M.G.), Yale University School of Medicine, New Haven, Conn; the Department of Histology and Embryology (G.T.), Akdeniz University, Antalya, Turkey; and the Department of Neurosurgery (H.Y., R.F.), Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Murat Gunel, MD, Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06510. E-mail murat.gunel{at}yale.edu

Background and Purpose— Mutations in the Programmed Cell Death 10 (PDCD10) gene cause autosomal dominant familial cerebral cavernous malformations (CCM3). To date, little is known about the function of this gene and its role in disease pathogenesis.

Methods— We examined the effects of overexpression of wild-type and 2 human disease-causing variants of PDCD10 on cell death using 3 different methods (TUNEL and MTT assays and caspase-3 activation). We analyzed expression of CCM3, activated caspase-3, and p38 in endothelial cell lines using the serum deprivation model of apoptosis induction. Finally, we assayed the effects of siRNA-mediated inhibition of endogenous PDCD10 expression on cell death in endothelial cell cultures.

Results— Overexpression of wild-type CCM3, but not disease-linked mutant forms, induced apoptosis as confirmed by TUNEL and increased levels of activated caspase-3. Serum starvation of endothelial cells, an inducer of apoptosis, led to increased expression of CCM3 and activation of p38 and ultimately activated caspase-3. siRNA-mediated inhibition of CCM3 expression resulted in decreased levels of p38 and activated caspase-3, and decreased cell death.

Conclusions— CCM3 is both necessary and sufficient to induce apoptosis in vitro in well-defined cell culture systems. Even though it is currently unclear whether this effect on apoptosis is direct or indirect through modulation of cell cycle, these results led to the novel hypothesis that CCM lesions may form as a consequence of aberrant apoptosis, potentially altering the balance between the endothelium and neural cells within the neurovascular unit.

Key Words: cerebral cavernous malformations • CCM3 • PDCD10 • apoptosis • p38 • caspase-3