Tremblay J J, Lanctôt C, Drouin J
Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, Québec, Canada.
Mol Endocrinol. 1998 Mar;12(3):428-41. doi: 10.1210/mend.12.3.0073.
The Ptx1 (pituitary homeobox 1) homeobox transcription factor was isolated as a transcription factor of the pituitary POMC gene. In corticotrope cells that express POMC, cell-specific transcription is conferred in part by the synergistic action of Ptx1 with the basic helix-loop-helix factor NeuroD1. Since Ptx1 expression precedes pituitary development and differentiation, we investigated its expression and function in other pituitary lineages. Ptx1 is expressed in most pituitary-derived cell lines and as is the related Ptx2 (Rieger) gene. However, Ptx1 appears to be the only Ptx protein in corticotropes and the predominant one in gonadotrope cells. Most pituitary hormone-coding gene promoters are activated by Ptx1. Thus, Ptx1 appears to be a general regulator of pituitary-specific transcription. In addition, Ptx1 action is synergized by cell-restricted transcription factors to confer promoter-specific expression. Indeed, in the somatolactotrope lineage, synergism between Ptx1 and Pit1 is observed on the PRL promoter, and strong synergism between Ptx1 and SF-1 is observed in gonadotrope cells on the betaLH promoter but not on the alphaGSU (glycoprotein hormone alpha-subunit gene) and betaFSH promoters. Synergism between these two classes of factors is reminiscent of the interaction between the products of the Drosophila genes Ftz (fushi tarazu) and Ftz-F1. Antisense RNA experiments performed in alphaT3-1 cells that express the alphaGSU gene showed that expression of endogenous alphaGSU is highly dependent on Ptx1 whereas many other genes are not affected. Interestingly, the only other gene found to be highly dependent on Ptx1 for expression was the gene for the Lim3/Lhx3 transcription factor. Thus, these experiments place Ptx1 upstream of Lim3/Lhx3 in a cascade of regulators that appear to work in a combinatorial code to direct pituitary-, lineage-, and promoter-specific transcription.
垂体同源框1（Ptx1）同源框转录因子最初是作为垂体促黑素原（POMC）基因的转录因子被分离出来的。在表达POMC的促肾上腺皮质激素细胞中，细胞特异性转录部分是由Ptx1与碱性螺旋-环-螺旋因子NeuroD1的协同作用赋予的。由于Ptx1的表达先于垂体的发育和分化，我们研究了它在其他垂体系中的表达和功能。Ptx1在大多数垂体来源的细胞系中表达，相关的Ptx2（里格尔）基因也是如此。然而，Ptx1似乎是促肾上腺皮质激素细胞中唯一的Ptx蛋白，并且是促性腺激素细胞中的主要Ptx蛋白。大多数垂体激素编码基因的启动子都被Ptx1激活。因此，Ptx1似乎是垂体特异性转录的一般调节因子。此外，Ptx1的作用通过细胞限制性转录因子的协同作用来赋予启动子特异性表达。实际上，在生长催乳素细胞系中，在催乳素（PRL）启动子上观察到Ptx1和垂体特异性转录因子1（Pit1）之间的协同作用，在促性腺激素细胞中，在促黄体生成素β亚基（betaLH）启动子上观察到Ptxl和类固醇生成因子1（SF-1）之间有强烈的协同作用，但在糖蛋白激素α亚基（alphaGSU）和促卵泡生成素β亚基（betaFSH）启动子上没有。这两类因子之间的协同作用让人联想到果蝇基因分节基因（Ftz）和Ftz-F1产物之间的相互作用。在表达alphaGSU基因的αT3-1细胞中进行的反义RNA实验表明，内源性alphaGSU的表达高度依赖于Ptx1，而许多其他基因不受影响。有趣的是，发现的另一个在表达上高度依赖于Ptx1的基因是Lim3/Lhx3转录因子的基因。因此，这些实验将Ptx1置于Lim3/Lhx3上游形成一个调节因子级联，这些调节因子似乎以组合密码的方式起作用，以指导垂体、细胞系和启动子特异性转录。
