Transcription factors Pax6 and AP-2α interact to coordinate corneal epithelial repair by controlling expression of matrix metalloproteinase gelatinase B
Transcription factors Pax6 and AP-2α interact to coordinate corneal epithelial repair by controlling expression of matrix metalloproteinase gelatinase B
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DOI：
10.1128/mcb.24.1.245-257.2004
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发表时间：
2004-01-01
影响因子：
5.3
通讯作者：
Fini, ME
中科院分区：
文献类型：
--
作者：
Sivak, JM;West-Mays, JA;Fini, ME
Pax 6是一个含有转录因子的配对盒，位于控制眼睛发育的遗传层次的顶部。它继续在成人眼组织中表达，但其在这种能力中的作用尚不清楚。Pax 6存在于成人角膜上皮中，并且我们表明，当上皮在损伤后重新浮出角膜时，Pax 6的量在迁移前沿增加（J.M.西瓦克河Mohan，W. B。Rinehart，P. X.许河，巴西-地L. Maas和M. E.菲尼德夫222：41-54，2000）。我们还表明，Pax 6控制的基质金属蛋白酶，明胶酶B（凝胶B; MMP-9）在细胞培养转染研究的转录启动子的活性。gelB的表达在角膜上皮的迁移前沿开启，它协调和影响上皮再生的各个方面（R.莫汉，S. K. Chintala，J. C. Jung，W. V. Villar，F.麦凯布湖A. Russo，Y.李，B。E. McCarthy，K. R. Jester，M. Wang，H. G. Welgus，J. M.希普利河M.老先生，M。E. Fini，J.Biol.Chem.277：2065-2072）。我们在这里定义了两个积极作用的Pax 6响应元件在gelB启动子。Pax 6通过配对的DNA结合结构域直接结合到这些位点之一。它通过与AP-2 α的相互作用间接结合第二个位点，AP-2 α是一种转录因子，也对眼睛发育起控制作用。通过使用Pax 6配对结构域突变（Sey（+/-））杂合小鼠的角膜上皮再生模型，在体内检查Pax 6对gelB表达的控制。在这些小鼠中减少Pax 6剂量导致在迁移上皮前沿的gelB表达的丧失。这种效应与炎症增加和上皮再生率相关，这一发现与gelB基因敲除小鼠的表型一致。总之，这些数据表明Pax 6通过与AP-2 α的协同相互作用控制gelB启动子的活性，并支持Pax 6在成人角膜上皮的维持和修复中的积极作用。
Pax6 is a paired box containing transcription factor that resides at the top of a genetic hierarchy controlling eye development. It continues to be expressed in tissues of the adult eye, but its role in this capacity is unclear. Pax6 is present in the adult corneal epithelium, and we showed that the amount of Pax6 is increased at the migrating front as the epithelium resurfaces the cornea after injury (J. M. Sivak, R. Mohan, W. B. Rinehart, P. X. Xu, R. L. Maas, and M. E. Fini, Dev. Biol. 222:41-54, 2000). We also showed that Pax6 controls activity of the transcriptional promoter for the matrix metalloproteinase, gelatinase B (gelB; MMP-9) in cell culture transfection studies. gelB expression is turned on at the migrating epithelial front in the cornea, and it coordinates and effects aspects of epithelial regeneration (R. Mohan, S. K. Chintala, J. C. Jung, W. V. Villar, F. McCabe, L. A. Russo, Y. Lee, B. E. McCarthy, K. R. Wollenberg, J. V. Jester, M. Wang, H. G. Welgus, J. M. Shipley, R. M. Senior, and M. E. Fini, J. Biol. Chem. 277:2065-2072). We define here two positively acting Pax6 response elements in the gelB promoter. Pax6 binds directly to one of these sites through the paired DNA-binding domain. It binds the second site indirectly by interaction with AP-2alpha, a transcription factor that also exerts control over eye development. Pax6 control of gelB expression was examined in vivo by using a corneal reepithelialization model in mice heterozygous for a Pax6 paired-domain mutation (Sey(+/-)). A reduced Pax6 dosage in these mice resulted in a loss of gelB expression at the migrating epithelial front. This effect was correlated with an increase in inflammation and the rate of reepithelialization, a finding consistent with the phenotype of gelB knockout mice. Together, these data indicate that Pax6 controls activity of the gelB promoter through cooperative interactions with AP-2alpha and support an active role for Pax6 in maintenance and repair of the adult corneal epithelium.