S-adenosylmethionine limitation induces p38 mitogen-activated protein kinase and triggers cell cycle arrest in G1
S-adenosylmethionine limitation induces p38 mitogen-activated protein kinase and triggers cell cycle arrest in G1
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DOI：
10.1242/jcs.127811
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发表时间：
2014-01-01
影响因子：
4
通讯作者：
Kaiser, Peter
中科院分区：
文献类型：
--
作者：
Lin, Da-Wei;Chung, Benjamin P.;Kaiser, Peter
主要的甲基供体S-腺苷甲硫氨酸（SAM）对多种细胞途径都很重要，包括核酸、蛋白质和mRNA的59帽结构的甲基化，以及磷脂和多胺的生物合成。此外，由于SAM是染色质甲基化的辅因子，因此它是表观遗传标记建立和维持的重要代谢物。在这里，我们证明了当SAM水平变低时，细胞停止增殖。细胞周期停滞主要发生在细胞周期的G1期，并伴随有丝分裂原活化蛋白激酶p38（MAPK 14）的活化和随后MAPK活化蛋白激酶-2（MK 2）的磷酸化。令人惊讶的是，Cdk 4活性在细胞周期停滞期间保持高水平，而Cdk 2活性随着细胞周期蛋白E水平的降低而降低。细胞周期阻滞诱导SAM合成的药理学和遗传操作，通过抑制或下调蛋氨酸腺苷转移酶，分别。耗尽蛋氨酸，SAM的前体，从生长培养基诱导类似的细胞周期停滞。出乎意料的是，无论是甲硫氨酸消耗或抑制甲硫氨酸腺苷转移酶显着影响mTORC 1活性，表明SAM限制的细胞反应是独立于这个主要的营养感应途径。这些结果证明了G1细胞周期检查点，其响应于主要细胞甲基供体S-腺苷甲硫氨酸的限制水平。这个代谢检查点可能在维持表观遗传稳定性和一般细胞完整性方面发挥重要作用。
The primary methyl group donor S-adenosylmethionine (SAM) is important for a plethora of cellular pathways including methylation of nucleic acids, proteins, and the 59 cap structure of mRNAs, as well as biosynthesis of phospholipids and polyamines. In addition, because it is the cofactor for chromatin methylation, SAM is an important metabolite for the establishment and maintenance of epigenetic marks. Here, we demonstrate that cells halt proliferation when SAM levels become low. Cell cycle arrest occurs primarily in the G1 phase of the cell cycle and is accompanied by activation of the mitogen-activated protein kinase p38 (MAPK14) and subsequent phosphorylation of MAPK-activated protein kinase-2 (MK2). Surprisingly, Cdk4 activity remains high during cell cycle arrest, whereas Cdk2 activity decreases concomitantly with cyclin E levels. Cell cycle arrest was induced by both pharmacological and genetic manipulation of SAM synthesis through inhibition or downregulation of methionine adenosyltransferase, respectively. Depletion of methionine, the precursor of SAM, from the growth medium induced a similar cell cycle arrest. Unexpectedly, neither methionine depletion nor inhibition of methionine adenosyltransferase significantly affected mTORC1 activity, suggesting that the cellular response to SAM limitation is independent from this major nutrient-sensing pathway. These results demonstrate a G1 cell cycle checkpoint that responds to limiting levels of the principal cellular methyl group donor S-adenosylmethionine. This metabolic checkpoint might play important roles in maintenance of epigenetic stability and general cellular integrity.