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HEIDELBERG, 26 November 2015 – Researchers in Italy, Germany and the United States have identified a regulatory protein crucial for the development of Cerebral Cavernous Malformation – a severe and incurable disease mainly affecting the brain microvasculature. The results, which are published in EMBO Molecular Medicine, show that the KLF4 protein plays a central role in the development of CCM lesions.
Cerebral Cavernous Malformation (CCM) is caused by mutations in the CCM1, CCM2 or CCM3 genes, and is characterized by vascular lesions that can lead to cerebral haemorrhage. Previous research has shown that ablation of CCM1 in mice leads to CCM pathology via a mechanism called Endothelial-to-mesenchymal transition (EndMT). While considerable effort has gone into establishing that EndMT occurs and plays a role in a variety of pathologic conditions, its molecular triggers have not been well defined.
The scientists found that KLF4 – a zinc-finger transcription factor of the Kruppel-Like Factor family – is strongly upregulated in the lesions of CCM1 knockout mice.
“Our study demonstrates that the genetic inactivation of KLF4 blocks the development and progression of CCM lesions and prevents mouse mortality due to brain haemorrhage,” says EMBO Member Elisabetta Dejana of the Italian FIRC Institute of Molecular Oncology and the University of Milan, the corresponding author of the study. KLF4 functions as one of the reprogramming “Yamanaka factors” in pluripotent stem cell induction cocktails.
The CCM pathway is required in endothelial cells for normal cardiovascular development and to prevent postnatal vascular malformations. The malformations are usually located in the white matter (cortex) of the brain. CCM are present in up to 0.5% of the general population, and they account for a large proportion (8-15%) of all brain and spinal vascular malformations.
Presently, there are no pharmacological treatments to prevent development or reduce the size of existing CCMs. The study identifies novel potential pharmacological targets to prevent the progression of this disease.
The study was conducted by researchers of the Italian FIRC Institute of Molecular Oncology and the University of Milan, in collaboration with the Max Planck Institute for Molecular Medicine in Munster, Germany, University Hospitals Case Medical Center in Cleveland and University of Virginia, United States, and with the support of Telethon and the Italian Association for Cancer Research (AIRC).
KLF4 is a key determinant in the development and progression of Cerebral Cavernous Malformations
Roberto Cuttano, Noemi Rudini, Luca Bravi, Monica Corada, Costanza Giampietro, Eleanna Papa, Marco Francesco Morini, Luigi Maddaluno, Nicolas Baeyens, Ralf H.
Adams, Mukesh K. Jain, Gary K. Owens, Martin Schwartz, Maria Grazia Lampugnani and Elisabetta Dejana
Read the paper: http://embomolmed.embopress.org/cgi/doi/10.15252/emmm.201505433
doi: 10.15252/emmm.201505433
Further information on EMBO Molecular Medicine is available at www.embomolmed.embopress.org
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About EMBO
EMBO is an organization of more than 1700 leading researchers that promotes excellence in the life sciences. The major goals of the organization are to support talented researchers at all stages of their careers, stimulate the exchange of scientific information, and help build a European research environment where scientists can achieve their best work.
EMBO helps young scientists to advance their research, promote their international reputations and ensure their mobility. Courses, workshops, conferences and scientific journals disseminate the latest research and offer training in techniques to maintain high standards of excellence in research practice. EMBO helps to shape science and research policy by seeking input and feedback from our community and by following closely the trends in science in Europe.
For more information: www.embo.org
http://www.embo.org/news/research-news/research-news-2015/molecular-trigger-for-...
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