Holloway J M, Szeto D P, Scully K M, Glass C K, Rosenfeld M G
Howard Hughes Medical Institute, University of California, San Diego, La Jolla 90293-0648, USA.
Genes Dev. 1995 Aug 15;9(16):1992-2006. doi: 10.1101/gad.9.16.1992.
Transcriptional activation of the prolactin and growth hormone genes, occurring in a cell-specific fashion, requires short-range synergistic interactions between the pituitary-specific POU domain factor Pit-1 and other transcription factors, particularly nuclear receptors. Unexpectedly, we find that these events involve the gene-specific use of alternative Pit-1 synergy domains. Synergistic activation of the prolactin gene by Pit-1 and the estrogen receptor requires a Pit-1 amino-terminal 25-amino-acid domain that is not required for analogous synergistic activation of the growth hormone promoter. The action of this Pit-1 synergy domain is dependent on the presence of two of three tyrosine residues spaced by 6 amino acids and can be replaced by a comparable tyrosine-dependent trans-activation domain of an unrelated transcription factor (hLEF). The gene-specific utilization of this tyrosine-dependent synergy domain is conferred by specific Pit-1 DNA-binding sites that determine whether Pit-1 binds as a monomer or a dimer. Thus, the critical DNA site in the prolactin enhancer, where this domain is required, binds Pit-1 as a monomer, whereas the Pit-1 sites in the growth hormone gene, which do not utilize this synergy domain, bind Pit-1 as a dimer. The finding that the sequence of specific DNA sites dictates alternative Pit-1 synergy domain utilization based on monomeric or dimeric binding suggests an additional regulatory strategy for differential target gene activation in distinct cell types.
催乳素基因和生长激素基因的转录激活以细胞特异性方式发生，需要垂体特异性POU结构域因子Pit-1与其他转录因子，特别是核受体之间进行短程协同相互作用。出乎意料的是，我们发现这些事件涉及对Pit-1协同结构域的基因特异性使用。Pit-1和雌激素受体对催乳素基因的协同激活需要一个Pit-1氨基末端25个氨基酸的结构域，而生长激素启动子的类似协同激活则不需要该结构域。这个Pit-1协同结构域的作用取决于由6个氨基酸隔开的三个酪氨酸残基中的两个的存在，并且可以被一个不相关转录因子（hLEF）的类似酪氨酸依赖性反式激活结构域所取代。这种酪氨酸依赖性协同结构域的基因特异性利用是由特定的Pit-1 DNA结合位点赋予的，这些位点决定了Pit-1是以单体还是二聚体形式结合。因此，催乳素增强子中需要该结构域的关键DNA位点以单体形式结合Pit-1，而生长激素基因中不利用该协同结构域的Pit-1位点以二聚体形式结合Pit-1。特定DNA位点的序列根据单体或二聚体结合决定了Pit-1协同结构域的不同利用，这一发现提示了一种在不同细胞类型中差异激活靶基因的额外调控策略。
