Requirements for selective recruitment of Ets proteins and activation of mb-1/lg-α gene transcription by Pax-5 (BSAP)

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Abstract

Pax-5, a member of the paired domain family of transcription factors, is a key regulator of B lymphocyte-specific transcription and differentiation. A major target of Pax-5-mediated activation is the mb-1 gene, which encodes the essential transmembrane signaling protein Ig-α. Pax-5 recruits three members of the Ets family of transcription factors: Ets-1, Fli-1 and GABPα (with GABPβ1), to assemble ternary complexes on the mb-1 promoter in vitro. Using the Pax-5:Ets-1:DNA crystal structure as a guide, we defined amino acid requirements for transcriptional activation of endogenous mb-1 genes using a novel cell-based assay. Mutations in the β-hairpin/β-turn of the DNA-binding domain of Pax-5 demonstrated its importance for DNA sequence recognition and activation of mb-1 transcription. Mutations of amino acids contacting Ets-1 in the crystal structure reduced or blocked mb-1 promoter activation. One of these mutations, Q22A, resulted in greatly reduced mb-1 gene transcript levels, concurrent with the loss of its ability to recruit Fli-1 to bind the promoter in vitro. In contrast, the mutation had no effect on recruitment of the related Ets protein GABPα (with GABPβ1). These data further define requirements for Pax-5 function in vivo and reveal the complexity of interactions required for cooperative partnerships between transcription factors.

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Maier, H., Ostraat, R., Parenti, S., Fitzsimmons, D., Abraham, L. J., Garvie, C. W., & Hagman, J. (2003). Requirements for selective recruitment of Ets proteins and activation of mb-1/lg-α gene transcription by Pax-5 (BSAP). Nucleic Acids Research, 31(19), 5483–5489. https://doi.org/10.1093/nar/gkg785

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