Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
J Oncol. 2012;2012:951724. doi: 10.1155/2012/951724. Epub 2012 Mar 15.
The Akt family of serine/threonine protein kinases are key regulators of multiple aspects of cell behaviour, including proliferation, survival, metabolism, and tumorigenesis. Growth-factor-activated Akt signalling promotes progression through normal, unperturbed cell cycles by acting on diverse downstream factors involved in controlling the G1/S and G2/M transitions. Remarkably, several recent studies have also implicated Akt in modulating DNA damage responses and genome stability. High Akt activity can suppress ATR/Chk1 signalling and homologous recombination repair (HRR) via direct phosphorylation of Chk1 or TopBP1 or, indirectly, by inhibiting recruitment of double-strand break (DSB) resection factors, such as RPA, Brca1, and Rad51, to sites of damage. Loss of checkpoint and/or HRR proficiency is therefore a potential cause of genomic instability in tumor cells with high Akt. Conversely, Akt is activated by DNA double-strand breaks (DSBs) in a DNA-PK- or ATM/ATR-dependent manner and in some circumstances can contribute to radioresistance by stimulating DNA repair by nonhomologous end joining (NHEJ). Akt therefore modifies both the response to and repair of genotoxic damage in complex ways that are likely to have important consequences for the therapy of tumors with deregulation of the PI3K-Akt-PTEN pathway.
丝氨酸/苏氨酸蛋白激酶 Akt 家族是细胞行为的多个方面的关键调节因子，包括增殖、存活、代谢和肿瘤发生。生长因子激活的 Akt 信号通过作用于参与控制 G1/S 和 G2/M 转变的各种下游因子，促进正常、未受干扰的细胞周期的进展。值得注意的是，最近的几项研究还表明 Akt 参与调节 DNA 损伤反应和基因组稳定性。高 Akt 活性可以通过直接磷酸化 Chk1 或 TopBP1 或间接抑制双链断裂 (DSB) 切除因子（如 RPA、Brca1 和 Rad51）向损伤部位募集来抑制 ATR/Chk1 信号和同源重组修复 (HRR)。因此，在 Akt 活性高的肿瘤细胞中，检查点和/或 HRR 功能丧失是基因组不稳定的潜在原因。相反，Akt 以依赖于 DNA-PK 或 ATM/ATR 的方式被 DNA 双链断裂 (DSBs) 激活，并且在某些情况下可以通过刺激非同源末端连接 (NHEJ) 来促进 DNA 修复，从而有助于放射抗性。因此，Akt 以复杂的方式修饰对遗传毒性损伤的反应和修复，这可能对 PI3K-Akt-PTEN 通路失调的肿瘤的治疗产生重要影响。
