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A more recent version of this article appeared on October 10, 2003
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M302433200v1
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Papers In Press, published online ahead of print August 5, 2003
J. Biol. Chem, 10.1074/jbc.M302433200
Submitted on March 10, 2003
Revised on July 25, 2003
Accepted on August 5, 2003

Ras signaling and transcriptional synergy at a flexible Ets-1/Pit-1 composite DNA element is defined by the assembly of selective activation domains

Dawn L. Duval, Annie Jean, and Arthur Gutierrez-Hartmann

Department of Medicine and Endocrine, University of Colorado Health Sciences Center, Denver, CO 80262

Corresponding Author: dawn.duval{at}uchsc.edu

Pit-1 and Ets-1 binding to a composite element synergistically activates and targets Ras-Map kinase signaling to the rat prolactin (rPRL) promoter. These transcriptional responses appear to depend on three molecular features: organization of the Ets-1/Pit-1 composite element, physical interaction of these two factors via the Pit-1 homeodomain (amino acids (AA) 199-291) and the Ets-1 RIII region (AA 190-257), and assembly of their transcriptional activation domains (TADs). Here we show that the organization of the Ets-1/Pit-1 composite element tolerates significant flexibility with regards to Ras stimulation and synergy. Specifically, the putative monomeric Pit-1 binding site can be substituted with bone fide binding sites for either a Pit-1 monomer or dimer, and these sites tolerated a separation of 28-bp. Additionally, we show that the physical interaction of Ets-1 and Pit-1 is not required for Ras responsiveness or synergy, since block mutations of the Pit-1 interaction surface in Ets-1, which reduced Ets-1/Pit-1 binding in vitro, did not significantly affect Ets-1 stimulation of Ras responsiveness or synergy. We also show differential use of distinct TAD subtypes and Pit-1 TAD subregions to mediate either synergy or Ras responsiveness. Specifically, TADs from GAL4, VP16 or Ets-2 Region III linked to Ets-1 DNA binding domain (DBD) constructs restored synergy to these TAD/Ets-1 DBD fusions. Conversely, deletion of the defined Pit-1 TAD (AA 2-80) retained synergy, but not Ras responsiveness. Consequently, we further defined the Pit-1 amino-terminal TAD into region 1 (R1: AA 2-45) and region 2 (R2: AA 46-80). R1 appears to regulate basal and synergistic responses, while the Ras response was mapped to R2. In summary, Ras responsiveness and Pit-1/Ets-1 synergy are mediated through the assembly of distinct TADs at a flexible composite element, indicating that different mechanisms underlie these two transcriptional responses and that the Pit-1 R2 subregion represents a novel, tissue-specific Ras-responsive TAD


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