Nuclear Receptor-Mediated Transactivation Through Interaction with Sp Proteins1 1 Arnt, AhR nuclear translocator; AhR, aryl hydrocarbon receptor; CKB, creatine kinase B; DRE, dioxin response element; ER, estrogen receptor; EREs, estrogen responsive elements; NRs, nuclear receptors; PPARs, peroxisome proliferator-activated receptors; RAR, retinoid acid receptor; RXR, retinoid X receptor; Sp1, ...

Title full: Nuclear Receptor-Mediated Transactivation Through Interaction with Sp Proteins1 1 Arnt, AhR nuclear translocator; AhR, aryl hydrocarbon receptor; CKB, creatine kinase B; DRE, dioxin response element; ER, estrogen receptor; EREs, estrogen responsive elements; NRs, nuclear receptors; PPARs, peroxisome proliferator-activated receptors; RAR, retinoid acid receptor; RXR, retinoid X receptor; Sp1, specificity protein 1; SF-1, steroidgenic factor-1; TBP, TATA-binding protein; TAFs, TATA-binding protein-associated factors; TGFβ, transforming growth factor β. The Sp{plus 45 degree rule}KLF family of nuclear transcription factors plays an important role in regulating gene expression in multiple cell lines. Constitutive expression of several genes is dependent on Sp1 and other family members which interact with proteins associated with the basal transcription machinery, including TAFs, TBP, and mediator complex proteins. Another level of transcriptional control involves cell context-dependent differences in expression of Sp{plus 45 degree rule}KLF proteins and their competitive binding to specific GC-rich promoters. These interactions can result in additive, synergistic, or antagonistic expression of genes and may depend, in part, on relative cellular expression of Sp proteins and their interactions with cis promoter elements. For example, Sp1 and Sp3 can cooperatively activate gene expression or Sp3 can inhibit Sp1-dependent transactivation, and these interactions are promoter- and cell context-dependent. Interactions of Sp1 with other DNA-bound transcription factors including ERα have been extensively described and are also important for gene regulation. The major focus of this review has been hormone-dependent activation of ERα{plus 45 degree rule}Sp1 through specific GC-rich promoter sequences and the contributions of this pathway to growth of ER-positive breast cancer cells. The results clearly demonstrate that this nonclassical genomic pathway may be a critical determinant for hormone-dependent cell growth. It was also evident that the mechanism of ERα{plus 45 degree rule}Sp1-mediated transactivation was different from that described for activation of ERα on ERE promoters. Domains of ERα required for ERα{plus 45 degree rule}Sp1 and ERα (on an ERE)-mediated transactivation and the effect of ER ligands (e.g., estrogens and antiestrogens) are different. Moreover, the p160 coactivators that exhibit ligand-dependent interactions with the AF2 region of ERα and coactivate ERα (on an ERE) inhibit ERα{plus 45 degree rule}Sp1-mediated transactivation in breast cancer cells (178). These results suggest that the as yet unidentified coactivators of ERα{plus 45 degree rule}Sp1 may be critical factors for growth of breast cancer cells, and the identities of coactivators and mechanisms of ERα{plus 45 degree rule}Sp1 coactivation are currently being investigated. It is also apparent that other nuclear receptors activate gene expression through interactions with Sp1. Differences in cell phenotypes are related, in part, to differences in their patterns of gene expression which, in turn, are dependent on coordinated expression of transcription factors and other nuclear coregulatory proteins. Sp1{plus 45 degree rule}KLF proteins typify the increasing complexities that have been revealed for this and other families of transcription factors. Sp proteins not only regulate basal expression of diverse mammalian and viral genes, but also form interacting networks with many other nuclear proteins to modulate gene expression. The studies with ERα{plus 45 degree rule}Sp1 have revealed a unique genomic mechanism of ERα action in breast cancer cells, and reports from several laboratories show that other members of the NR family also act through NR{plus 45 degree rule}Sp protein complexes. Current research is focused on contributions of this pathway in mediating gene expression in normal cells{plus 45 degree rule}tissues using both in vitro and in vivo models.