Research with Prominent Academic and Industry Scientists Published in The Journal Molecular and Cellular Biology
A new discovery about how the extracellular environment affects the regulation of gene expression may have important implications in the ways doctors understand and treat diseases like atherosclerosis, psoriasis, stroke and cancer. The study, which was published in the August issue of the journal Molecular and Cellular Biology (vol. 22, no. 16), advances the basic understanding of the signaling pathways and gene expression changes that allow a coordinated regulation of angiogenesis and inflammation by endothelial cells.
The study was conducted by a team of scientists from academia and industry. Filippo Giancotti, M.D., Ph.D., of Memorial Sloan-Kettering Cancer Center was the senior author. Research teams at Biogen (Nasdaq: BGEN) and CuraGen Corporation (Nasdaq: CRGN) collaborated with the Memorial Sloan-Kettering team.
The authors examined the effect that the extracellular environment can have on cells, and found that the protein fibronectin (found in the extracellular matrix) is capable of specifically controlling expression of genes which play a pivotal role in inflammation and angiogenesis. The scientists have identified the intracellular mechanism involved and demonstrated in vivo its importance for angiogenesis.
The study authors used GeneCalling®, a genome-wide method of mRNA profiling, to further understand the process by which endothelial cells adhere to extracellular matrix proteins fibronectin and laminin. GeneCalling is a patented gene expression technology developed by CuraGen Corporation. Adhesion of endothelial cells to extracellular matrix proteins occurs through engagement of a family of cell surface receptors known collectively as integrins, and results in the subsequent activation of a complex program of gene expression. Integrins have multiple adhesive and signaling functions that may play a crucial role in angiogenesis and inflammation. The authors found that attachment of human endothelial cells to extracellular matrix proteins, in particular fibronectin, can provide very potent regulation of gene expression. Many of the identified genes are considered highly significant to angiogenesis and inflammation.
One of the most novel aspects of this work is the discovery of how integrin-related signaling pathways, which have been extensively studied by Dr. Giancotti, are involved in the regulation of a program of gene expression important for angiogenesis and inflammation. Adhesion of endothelial cells to fibronectin through the 51 integrin, but not to laminin through the 21 integrin, activates gene transcription. This occurs through a signaling pathway requiring several well-known intracellular proteins, including Ras, phosphatidylinositol 3-kinase, and members of the Rho family.
Commenting on the group’s findings, Biogen’s Victor E. Koteliansky, M.D. Ph.D., and Dr. Antonin de Fougerolles, Ph.D., said, “We are very pleased to have been able to collaborate on this work with Dr. Giancotti and his colleagues at Memorial Sloan-Kettering, as well as with researchers from CuraGen Corporation. We are excited to further our understanding of how the environment in which cells reside affects their biological function. These interactions occur largely through integrin proteins, in which Biogen has had a long-standing interest. We have now successfully described on a comprehensive basis how extracellular matrix can affect endothelial cell function and dissected the molecular signaling pathways responsible. This study takes us another step closer to finding new and improved ways to regulate angiogenesis and inflammation.”
Angiogenesis is the formation of new blood vessels from pre-existing ones. It requires endothelial cells to migrate, proliferate and assemble into tubes that regulate selective transport of white blood cells and solutes. Several observations suggest that angiogenesis and inflammation proceed in a coordinated fashion and sustain one another during wound healing and tissue repair, as well as in cancer and a variety of chronic inflammatory diseases.
Biogen, Inc., winner of the U.S. National Medal of Technology, is a biotechnology
company principally engaged in discovering and developing drugs for human healthcare through genetic engineering. Headquartered in Cambridge, MA, the Company’s revenues are generated from U.S. and European sales of AVONEX® (Interferon beta-1a) for treatment of relapsing forms of multiple sclerosis, (please see full prescribing information at http://www.avonex.com.), and from the worldwide sales by licensees of a number of products, including alpha interferon and hepatitis B vaccines and diagnostic products. Biogen’s research and development activities are focused on novel products to treat inflammatory and autoimmune diseases, neurological diseases, cancer, fibrosis, and congestive heart failure. The Company maintains active clinical research programs in protein therapeutics, small molecules, genomics and gene therapy. For copies of press releases and additional information about the Company, please consult Biogen’s homepage on the World Wide Web at http://www.biogen.com.
About Memorial Sloan-Kettering Cancer Center
Memorial Sloan-Kettering Cancer Center is the world’s oldest and largest institution devoted to prevention, patient care, research and education in cancer. Their scientists and clinicians generate innovative approaches to better understand, diagnose and treat cancer. Memorial Sloan-Kettering’s specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide.
CuraGen Corporation (NASDAQ: CRGN) is a genomics-based pharmaceutical company. CuraGen’s integrated, functional genomic technologies and Internet-based bioinformatic systems are designed to generate comprehensive information about genes, human genetic variations, gene expression, protein interactions, protein pathways, and potential drugs that affect these pathways. The Company is applying its industrialized genomic technologies, informatics, and validation technologies to develop protein, antibody, and small molecule therapeutics to treat obesity and diabetes, cancer, inflammatory diseases, and central nervous system (CNS) disorders. CuraGen is headquartered in New Haven, CT. Additional information is available at www.curagen.com.
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