Edwards Dean P, Wardell Suzanne E, Boonyaratanakornkit Viroj
Program in Molecular Biology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, B216 Denver, CO 80262, USA.
J Steroid Biochem Mol Biol. 2002 Dec;83(1-5):173-86. doi: 10.1016/s0960-0760(02)00265-0.
Progesterone receptor (PR) is a member of the nuclear receptor family of ligand-dependent transcription activators and is expressed as two different sized proteins from a single gene; PR-A and PR-B. The two PR isoforms are identical in their DNA binding domains (DBD) and C-terminal ligand binding domains (LBD), differing only in the N-terminal domain that is truncated in PR-A. PR also contains two autonomous transcription activation domains (AD), ligand-dependent AF-2 in the C-terminus and constitutive AF-1 in the N-terminus. AF-2 is highly conserved and a family of p160 coactivators that interacts with and mediates the activity of AF-2 has been well characterized. By contrast the N-terminal domain and AF-1 are not conserved and little is known about AF-1 coactivators. The N-terminal domain is functionally important as it is required for full transcription activity of PR and is responsible for the distinct activities of the two PR isoforms, as well as cell and promoter specific functions of PR. This paper describes our efforts to identify PR N-terminal interacting coregulatory proteins. We summarize our work on the role of jun dimerization protein-2 (JDP-2) as an AF-1 coactivator of PR. JDP-2, initially defined as a repressor of jun and other bZIP transcription factors, also functions as a potent PR selective coactivator. JDP-2 lacks an intrinsic activation domain and through association with the DBD, we propose that JDP-2 potentiates AF-1 by recruiting other coactivators independent of AF-2 and p160 pathways. We also discovered that PR contains an SH3 domain interaction motif in the N-terminus that mediates interaction with Src tyrosine kinases and other signaling molecules. This interaction mediates rapid progesterone activation of Src/MAP K signaling pathways and defines a molecular mechanism for some of the rapid non-genomic actions of progesterone.
孕激素受体（PR）是配体依赖性转录激活因子核受体家族的成员，由单个基因表达为两种不同大小的蛋白质；PR-A和PR-B。这两种PR异构体在其DNA结合结构域（DBD）和C端配体结合结构域（LBD）中是相同的，仅在PR-A中被截断的N端结构域有所不同。PR还包含两个自主转录激活结构域（AD），C端的配体依赖性AF-2和N端的组成型AF-1。AF-2高度保守，与AF-2相互作用并介导其活性的p160共激活因子家族已得到充分表征。相比之下，N端结构域和AF-1并不保守，对AF-1共激活因子了解甚少。N端结构域在功能上很重要，因为它是PR完全转录活性所必需的，并且负责两种PR异构体的不同活性，以及PR的细胞和启动子特异性功能。本文描述了我们识别PR N端相互作用共调节蛋白的努力。我们总结了关于jun二聚化蛋白-2（JDP-2）作为PR的AF-1共激活因子的作用的工作。JDP-2最初被定义为jun和其他bZIP转录因子的抑制剂，也作为一种有效的PR选择性共激活因子发挥作用。JDP-2缺乏内在激活结构域，通过与DBD结合，我们提出JDP-2通过招募独立于AF-2和p160途径的其他共激活因子来增强AF-1。我们还发现PR在N端含有一个SH3结构域相互作用基序，介导与Src酪氨酸激酶和其他信号分子的相互作用。这种相互作用介导了Src/MAP K信号通路的快速孕激素激活，并定义了孕激素一些快速非基因组作用的分子机制。
