TY  - JOUR
A1  - Chapman, Eric M.
A1  - Lant, Benjamin
A1  - Ohashi, Yota
A1  - Yu, Bin
A1  - Schertzberg, Michael
A1  - Go, Christopher
A1  - Dogra, Deepika
A1  - Koskimaki, Janne
A1  - Girard, Romuald
A1  - Li, Yan
A1  - Fraser, Andrew G.
A1  - Awad, Issam A.
A1  - Abdelilah-Seyfried, Salim
A1  - Gingras, Anne-Claude
A1  - Derry, William Brent
T1  - A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis
JF  - Nature Communications
N2  - Apoptotic death of cells damaged by genotoxic stress requires regulatory input from surrounding tissues. The C. elegans scaffold protein KRI-1, ortholog of mammalian KRIT1/CCM1, permits DNA damage-induced apoptosis of cells in the germline by an unknown cell non-autonomous mechanism. We reveal that KRI-1 exists in a complex with CCM-2 in the intestine to negatively regulate the ERK-5/MAPK pathway. This allows the KLF-3 transcription factor to facilitate expression of the SLC39 zinc transporter gene zipt-2.3, which functions to sequester zinc in the intestine. Ablation of KRI-1 results in reduced zinc sequestration in the intestine, inhibition of IR-induced MPK-1/ERK1 activation, and apoptosis in the germline. Zinc localization is also perturbed in the vasculature of krit1(-/-) zebrafish, and SLC39 zinc transporters are mis-expressed in Cerebral Cavernous Malformations (CCM) patient tissues. This study provides new insights into the regulation of apoptosis by cross-tissue communication, and suggests a link between zinc localization and CCM disease.
Y1  - 2019
U6  - https://doi.org/10.1038/s41467-019-09829-z
SN  - 2041-1723
VL  - 10
PB  - Nature Publ. Group
CY  - London
ER  - 
TY  - JOUR
A1  - Otten, Cecile
A1  - Knox, Jessica
A1  - Boulday, Gwenola
A1  - Eymery, Mathias
A1  - Haniszewski, Marta
A1  - Neuenschwander, Martin
A1  - Radetzki, Silke
A1  - Vogt, Ingo
A1  - Haehn, Kristina
A1  - De Luca, Coralie
A1  - Cardoso, Cecile
A1  - Hamad, Sabri
A1  - Igual Gil, Carla
A1  - Roy, Peter
A1  - Albiges-Rizo, Corinne
A1  - Faurobert, Eva
A1  - von Kries, Jens P.
A1  - Campillos, Monica
A1  - Tournier-Lasserve, Elisabeth
A1  - Derry, William Brent
A1  - Abdelilah-Seyfried, Salim
T1  - Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations
JF  - EMBO molecular medicine
N2  - Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non-invasive pharmacological therapies. Here, we present the results of several unbiased small-molecule suppression screens in which we applied a total of 5,268 unique substances to CCM mutant worm, zebrafish, mouse, or human endothelial cells. We used a systems biology-based target prediction tool to integrate the results with the whole-transcriptome profile of zebrafish CCM2 mutants, revealing signaling pathways relevant to the disease and potential targets for small-molecule-based therapies. We found indirubin-3-monoxime to alleviate the lesion burden in murine preclinical models of CCM2 and CCM3 and suppress the loss-of-CCM phenotypes in human endothelial cells. Our multi-organism-based approach reveals new components of the CCM regulatory network and foreshadows novel small-molecule-based therapeutic applications for suppressing this devastating disease in patients.
KW  - angiogenesis
KW  - CCM
KW  - ERK5
KW  - indirubin-3-monoxime
KW  - KLF2
Y1  - 2018
U6  - https://doi.org/10.15252/emmm.201809155
SN  - 1757-4676
SN  - 1757-4684
VL  - 10
IS  - 10
PB  - Wiley
CY  - Hoboken
ER  -