Distinct Role of Kruppel-like Factor 11 in the Regulation of Prostaglandin E2 Biosynthesis
Distinct Role of Kruppel-like Factor 11 in the Regulation of Prostaglandin E2 Biosynthesis
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DOI：
10.1074/jbc.m109.077065
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发表时间：
2010-04-09
影响因子：
4.8
通讯作者：
Urrutia, Raul
中科院分区：
文献类型：
--
作者：
Buttar, Navtej S.;DeMars, Cathrine J.;Urrutia, Raul
Kruppel样因子（KLF）蛋白是脂代谢、糖尿病和免疫细胞因子生物合成的关键调节因子。然而，它们在合成三尖杉酯碱中的作用仍然知之甚少，三尖杉酯碱是广泛已知的生化介质，在无数的细胞生物学过程中起作用。因此，在这项研究中，在细胞，生物化学和分子水平的综合研究表明，KLF 11抑制前列腺素E-2的合成通过其生物合成酶，胞浆磷脂酶A2 α的启动子的转录沉默。从机制上讲，KLF 11通过特定的富含GC的位点与启动子结合并募集Sin 3-组蛋白脱乙酰酶染色质重塑复合物来实现这一功能。进一步的功能表征表明，KLF 11的这种功能可以通过表皮生长因子受体-AKT介导的苏氨酸56（其Sin 3结合结构域内的残基）的翻译后修饰来逆转。这是第一个证据支持相关的作用，任何KLF蛋白在做两个：转录抑制前列腺素的生物合成和其可逆性的表皮生长因子受体AKT信号介导的翻译后机制。
Kruppel-like factor (KLF) proteins are emerging as key regulators of lipid metabolism, diabetes, and the biosynthesis of immunological cytokines. However, their role in the synthesis of prostaglandins, widely known biochemical mediators that act in a myriad of cell biological processes remain poorly understood. Consequently, in this study a comprehensive investigation at the cellular, biochemical, and molecular levels reveal that KLF11 inhibits prostaglandin E-2 synthesis via transcriptional silencing of the promoter of its biosynthetic enzyme, cytosolic phospholipase A2 alpha. Mechanistically, KLF11 accomplishes this function by binding to the promoter via specific GC-rich sites and recruiting the Sin3-histone deacetylase chromatin remodeling complex. Further functional characterization reveals that this function of KLF11 can be reversed by epidermal growth factor receptor-AKT-mediated post-translational modification of threonine 56, a residue within its Sin3-binding domain. This is the first evidence supporting a relevant role for any KLF protein in doing both: transcriptionally inhibiting prostaglandin biosynthesis and its reversibility by an epidermal growth factor receptor-AKT signaling-mediated posttranslational mechanisms.