Chemical control of protein stability and function in living mice View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2008-10

AUTHORS

Laura A Banaszynski, Mark A Sellmyer, Christopher H Contag, Thomas J Wandless, Steve H Thorne

ABSTRACT

Conditional control of protein function in vivo offers great potential for deconvoluting the roles of individual proteins in complicated systems. We recently developed a method in which a small protein domain, termed a destabilizing domain, confers instability to fusion protein partners in cultured cells. Instability is reversed when a cell-permeable small molecule binds this domain. Here we describe the use of this system to regulate protein function in living mammals. We show regulation of secreted proteins and their biological activity with conditional secretion of an immunomodulatory cytokine, resulting in tumor burden reduction in mouse models. Additionally, we use this approach to control the function of a specific protein after systemic delivery of the gene that encodes it to a tumor, suggesting uses for enhancing the specificity and efficacy of targeted gene-based therapies. This method represents a new strategy to regulate protein function in living organisms with a high level of control. More... »

PAGES

1123-1127

Journal

TITLE

Nature Medicine

ISSUE

10

VOLUME

14

Author Affiliations

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nm.1754

DOI

http://dx.doi.org/10.1038/nm.1754

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https://app.dimensions.ai/details/publication/pub.1025409682

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/18836461


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50 schema:description Conditional control of protein function in vivo offers great potential for deconvoluting the roles of individual proteins in complicated systems. We recently developed a method in which a small protein domain, termed a destabilizing domain, confers instability to fusion protein partners in cultured cells. Instability is reversed when a cell-permeable small molecule binds this domain. Here we describe the use of this system to regulate protein function in living mammals. We show regulation of secreted proteins and their biological activity with conditional secretion of an immunomodulatory cytokine, resulting in tumor burden reduction in mouse models. Additionally, we use this approach to control the function of a specific protein after systemic delivery of the gene that encodes it to a tumor, suggesting uses for enhancing the specificity and efficacy of targeted gene-based therapies. This method represents a new strategy to regulate protein function in living organisms with a high level of control.
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