Higashimoto Ken, Kuhn Peter, Desai Dhaval, Cheng Xiaodong, Xu Wei
McArdle Laboratory for Cancer Research, University of Wisconsin, 1400 University Avenue, Madison, WI 53706, USA.
Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12318-23. doi: 10.1073/pnas.0610792104. Epub 2007 Jul 17.
Multiple protein arginine methyltransferases are involved in transcriptional activation of nuclear receptors. Coactivator-associated arginine methyltransferase 1 (CARM1)-mediated histone methylation has been shown to activate nuclear receptor-dependent transcription; however, little is known about the regulation of its enzymatic activity. Here, we report that the methyltransferase activity of CARM1 is negatively regulated through phosphorylation at a conserved serine residue. When the serine residue is mutated to glutamic acid, which mimics the phosphorylated serine residue, the mutant CARM1 exhibits diminished ability to bind the methyl donor adenosylmethionine and diminished histone methylation activity. Moreover, such mutation leads to the inhibition of CARM1 transactivation of estrogen receptor-dependent transcription. Our results provide an example for the regulation of protein arginine methyltransferase activity by phosphorylation. As CARM1 is a potent transcriptional coactivator of estrogen receptor, our results suggest that phosphorylation of CARM1 serves as a unique mechanism for inactivating CARM1-regulated estrogen-dependent gene expression.
多种蛋白质精氨酸甲基转移酶参与核受体的转录激活。共激活因子相关精氨酸甲基转移酶1（CARM1）介导的组蛋白甲基化已被证明可激活核受体依赖性转录；然而，对其酶活性的调节知之甚少。在此，我们报告CARM1的甲基转移酶活性通过一个保守丝氨酸残基的磷酸化而受到负调控。当丝氨酸残基突变为谷氨酸（模拟磷酸化的丝氨酸残基）时，突变型CARM1结合甲基供体腺苷甲硫氨酸的能力减弱，组蛋白甲基化活性降低。此外，这种突变导致CARM1对雌激素受体依赖性转录的反式激活受到抑制。我们的结果为通过磷酸化调节蛋白质精氨酸甲基转移酶活性提供了一个实例。由于CARM1是雌激素受体的一种强效转录共激活因子，我们的结果表明CARM1的磷酸化是使CARM1调节的雌激素依赖性基因表达失活的一种独特机制。
