Mechanisms of G2 arrest in response to overexpression of p53
Mechanisms of G2 arrest in response to overexpression of p53
复制标题
DOI：
10.1091/mbc.10.11.3607
复制
发表时间：
1999-11-01
影响因子：
3.3
通讯作者：
Stark, GR
中科院分区：
文献类型：
--
作者：
Taylor, WR;DePrimo, SE;Stark, GR
p53 的过度表达会导致 G2 期停滞，部分原因是 CDC2 活性丧失。使用由两个启动子驱动的报告构建体确定的 cdc2 和细胞周期蛋白 BI 的转录响应 p53 的诱导而受到抑制。抑制需要细胞周期蛋白 B1 启动子的 -287 至 -123 区域和 cdc2 启动子的 -104 至 -74 区域。 p53 不影响 CDC2 在苏氨酸 14 或酪氨酸 15 处的抑制性磷酸化，也不影响通过在苏氨酸 161 处磷酸化 CDC2 来激活 CDC2 的细胞周期蛋白依赖性激酶的活性。p53 的过度表达还可能干扰细胞进入有丝分裂所需的 CDC2/细胞周期蛋白 B1 在细胞核中的积累。细胞周期蛋白 B1 的组成型表达，单独或与组成型活性 CDC2 蛋白 T14A Y15F 组合，不会逆转 p53 依赖性 G2 停滞。然而，将细胞周期蛋白 B1 靶向也表达 CDC2 T14A Y15F 的细胞的细胞核确实克服了这种停滞。几种不同的途径可能导致 p53 依赖性 G2 停滞。
Overexpression of p53 causes G2 arrest, attributable in part to the loss of CDC2 activity. Transcription of cdc2 and cyclin BI, determined using reporter constructs driven by the two promoters, was suppressed in response to the induction of p53. Suppression requires the regions -287 to -123 of the cyclin B1 promoter and -104 to -74 of the cdc2 promoter. p53 did not affect the inhibitory phosphorylations of CDC2 at threonine 14 or tyrosine 15 or the activity of the cyclin-dependent kinase that activates CDC2 by phosphorylating it at threonine 161. Overexpression of p53 may also interfere with the accumulation of CDC2/cyclin B1 in the nucleus, required for cells to enter mitosis. Constitutive expression of cyclin B1, alone or in combination with the constitutively active CDC2 protein T14A Y15F, did not reverse p53-dependent G2 arrest. However, targeting cyclin B1 to the nucleus in cells also expressing CDC2 T14A Y15F did overcome this arrest. It is likely that several distinct pathways contribute to p53-dependent G2 arrest.