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Molecular and Cellular Biology, April 1999, p. 2913-2920, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Design of Conditionally Active STATs: Insights into STAT Activation and Gene Regulatory Function

Lawrence H. Milocco, Jennifer A. Haslam, Jonathan Rosen, and H. Martin Seidel*

Ligand Pharmaceuticals Inc., San Diego, California 92121

Received 10 September 1998/Returned for modification 16 November 1998/Accepted 6 January 1999

The STAT (signal transducer and activator of transcription) signaling pathway is activated by a large number of cytokines and growth factors. We sought to design a conditionally active STAT that could not only provide insight into basic questions about STAT function but also serve as a powerful tool to determine the precise biological role of STATs. To this end, we have developed a conditionally active STAT by fusing STATs with the ligand-binding domain of the estrogen receptor (ER). We have demonstrated that the resulting STAT-ER chimeras are estrogen-inducible transcription factors that retain the functional and biochemical characteristics of the cognate wild-type STATs. In addition, these tools have allowed us to evaluate separately the contribution of tyrosine phosphorylation and dimerization to STAT function. We have for the first time provided experimental data supporting the model that the only apparent role of STAT tyrosine phosphorylation is to drive dimerization, as dimerization alone is sufficient to unmask a latent STAT nuclear localization sequence and induce nuclear translocation, sequence-specific DNA binding, and transcriptional activity.

* Corresponding author. Mailing address: Ligand Pharmaceuticals Inc., 10275 Science Center Dr., San Diego, CA 92121. Phone: (619) 550-7657. Fax: (619) 550-7706. E-mail: mseidel{at}ligand.com.

Molecular and Cellular Biology, April 1999, p. 2913-2920, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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