The suppression of MAD1 by AKT-mediated phosphorylation activates MAD1 target genes transcription.
The suppression of MAD1 by AKT-mediated phosphorylation activates MAD1 target genes transcription.
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DOI：
10.1002/mc.20557
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发表时间：
2009-11
影响因子：
4.6
通讯作者：
Hung, Mien-Chie
中科院分区：
文献类型：
--
作者：
Chou, Chao-Kai;Lee, Dung-Fang;Sun, Hui-Lung;Li, Long-Yuan;Lin, Chun-Yi;Huang, Wei-Chien;Hsu, Jung-Mao;Kuo, Hsu-Ping;Yamaguchi, Hirohito;Wang, Ying-Nai;Liu, Mo;Wu, Hsin-Yi;Liao, Pao-Chi;Yen, Chia-Jui;Hung, Mien-Chie
MAX二聚化蛋白1(MAD1)是一种转录抑制因子，能拮抗MYC介导的转录激活，其抑制机制主要是通过MAD1竞争靶基因的启动子MYC结合位点来实现的。启动子结合蛋白在MYC和MAD1之间的转换影响细胞的增殖和分化。然而，对MAD1在癌细胞中的S调控过程知之甚少。在这里，我们提出证据表明，AKT通过与MAD1的物理作用和MAD1的磷酸化来抑制MAD1介导的转录抑制。磷酸化降低了MAD1与其靶基因启动子之间的结合亲和力，从而取消了其转录抑制功能。在激活的AKT存在的情况下，从丝氨酸到丙氨酸的磷酸化位点的突变挽救了DNA结合能力。此外，AKT还抑制MAD1介导的靶基因(hTERT和ODC)转录抑制，促进细胞周期和细胞生长。然而，突变的S145A MAD1可取消AKT的抑制作用。因此，我们的结果表明，AKT对MAD1的磷酸化抑制了MAD1介导的转录抑制，并随后激活了MAD1靶基因的转录。
MAX dimerization protein 1 (MAD1) is a transcription suppressor that antagonizes MYC-mediated transcription activation, and the inhibition mechanism occurs mainly through the competition of target genes' promoter MYC binding sites by MAD1. The promoter binding proteins switch between MYC and MAD1 affects cell proliferation and differentiation. However, little is known about MAD1's regulation process in cancer cells. Here, we present evidence that AKT inhibits MAD1-mediated transcription repression by physical interaction with and phosphorylation of MAD1. Phosphorylation reduces the binding affinity between MAD1 and its target genes' promoter and thereby abolishes its transcription suppression function. Mutation of the phosphorylation site from serine to alanine rescues the DNA-binding ability in the presence of activated AKT. In addition, AKT inhibits MAD1 mediated target genes (hTERT and ODC) transcription repression and promotes cell cycle and cell growth. However, mutated S145A MAD1 abrogates the inhibition by AKT. Thus, our results suggest that phosphorylation of MAD1 by AKT inhibits MAD1-mediated transcription suppression and subsequently activates the transcription of MAD1 target genes.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
2.6
作者：
Guo, Xiao-Ling;Pan, Ling;Ohno, Ruzo
通讯作者：
Ohno, Ruzo
影响因子：
7.5
作者：
Downward, J
通讯作者：
Downward, J
影响因子：
5.3
作者：
Barrera-Hernandez, G;Cultraro, CM;Segal, S
通讯作者：
Segal, S
DOI：
10.1073/pnas.071043198
发表时间：
2001-03-27
影响因子：
11.1
作者：
Xu, DW;Popov, N;Henriksson, M
通讯作者：
Henriksson, M