Abstract Title

Dimerization Enhances Transcriptional Activity of Notch 4

Additional Funding Sources

This project is supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award No. R25GM123927.

Abstract

Notch 4 is the most unique and least well understood of the four receptors in Notch cell signaling, a pathway involved in regulating aspects of development and adult homeostasis in all multicellular organisms. Notch 4 is almost exclusively expressed in endothelial vascular cells and is thought to regulate angiogenesis, a process that is misregulated in many forms of disease, including cancer. Notch 4 proteins are able to dimerize and affect transcription rates of target genes, but the relationship between dimerization and transcriptional activity has yet to be experimentally tested. This study investigates this relationship using luciferase reporter assays to compare the transcriptional activity of wild-type Notch 4 to a mutant Notch 4 that can’t dimerize due to having its dimerization-enhancing domain deleted. The results show that the transcriptional activity of mutant Notch 4 decreases, on average, by almost 50%, indicating that there is a strong relationship between Notch 4 dimerization and transcriptional activity. This finding uncovers details about the molecular mechanisms by which Notch 4 functions, potentially helping to work towards new ideas about how Notch 4 could be targeted to treat conditions relating to misregulated angiogenesis.

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Dimerization Enhances Transcriptional Activity of Notch 4

Notch 4 is the most unique and least well understood of the four receptors in Notch cell signaling, a pathway involved in regulating aspects of development and adult homeostasis in all multicellular organisms. Notch 4 is almost exclusively expressed in endothelial vascular cells and is thought to regulate angiogenesis, a process that is misregulated in many forms of disease, including cancer. Notch 4 proteins are able to dimerize and affect transcription rates of target genes, but the relationship between dimerization and transcriptional activity has yet to be experimentally tested. This study investigates this relationship using luciferase reporter assays to compare the transcriptional activity of wild-type Notch 4 to a mutant Notch 4 that can’t dimerize due to having its dimerization-enhancing domain deleted. The results show that the transcriptional activity of mutant Notch 4 decreases, on average, by almost 50%, indicating that there is a strong relationship between Notch 4 dimerization and transcriptional activity. This finding uncovers details about the molecular mechanisms by which Notch 4 functions, potentially helping to work towards new ideas about how Notch 4 could be targeted to treat conditions relating to misregulated angiogenesis.