p38 MAP kinase in early thymocyte development

项目总结/摘要 虽然双链断裂（DSB）通常是对刺激产生的， 损伤时，它们也在经历V（D）J的未成熟胸腺细胞（DN 3期）中连续产生 重组而编码端通过非同源末端连接被快速加工和重新连接 （NHEJ）途径在G1/S细胞周期检查点，我们已经表明，信号结束（从切除的DSB DNA片段）保留在G1后DN 3胸腺细胞中。这些信号末端可以随机整合到基因组中 导致基因组不稳定，可能导致T细胞恶性肿瘤。我们已经证明，p38 MAP激酶（MAPK） 在DN 3胸腺细胞中诱导G2/M细胞周期检查点。我们相信这个G2/M细胞周期检查点是 由于信号末端的存在而触发，因此必须修复这些DSB并防止其整合 从而防止基因组的不稳定性我们最近的研究表明p38的激活 MAPK对DSB的反应导致该激酶优先核定位。我们还表明， p38 MAPK通过磷酸化GSK 3激活连环蛋白/存活通路。我们建议 DN 3胸腺细胞中信号末端的存在导致p38 MAPK的活化和核积累， p38 MAPK通路在促进信号末端修复和阻止其表达中起着关键作用。 随机整合到基因组中：1）诱导信号末端的G2/M细胞周期检查点， 在细胞分裂之前修复，和2）在经历G2/M期时诱导DN 3胸腺细胞的存活。 细胞周期检查点我们将研究：1）信号末端激活p38 MAPK是否促进 p38 MAPK通过与NBS 1结合诱导G2/M细胞周期检查点的核积累 在DN 3胸腺细胞中（目的1），p38 MAPK促进DN 3胸腺细胞的存活，同时经历G2/M细胞 通过磷酸化和GSK 3？失活的周期检查点（目的2），3）p38 MAPK的激活， G2/M期细胞周期检查点的建立对于修复信号末端和阻止整合是必需的 的信号关节进入基因组（目的3）。

Project Summary/Abstract Although double stranded breaks (DSBs) are normally generated in response to stimuli that cause DNA damage, they are also continuously generated in immature thymocytes (DN3 stage) undergoing V(D)J recombination. While coding ends are processed and re-joined quickly by the non-homologous end-joining (NHEJ) pathway at the G1/S cell cycle checkpoint, we have shown that signal ends (DSBs from the excised DNA fragment) remain in post-G1 DN3 thymocytes. These signal ends can randomly integrate in the genome causing genomic instability that may lead to T cell malignancies. We have shown that p38 MAP kinase (MAPK) induces a G2/M cell cycle checkpoint in DN3 thymocytes. We believe that this G2/M cell cycle checkpoint is triggered by the presence of signal ends and it is essential to repair these DSBs and prevent their integration into the genome, thereby preventing genomic instability. Our recent studies indicate that activation of p38 MAPK in response to DSBs causes a preferential nuclear localization of this kinase. We have also shown that p38 MAPK activates the ¿-catenin /survival pathway by phosporylation of GSK3¿. We propose that the presence of signal ends in DN3 thymocytes leads to activation and nuclear accumulation of p38 MAPK, and that p38 MAPK pathway plays a critical role in facilitating signal ends repair and preventing their random integration into the genome by: 1) inducing a G2/M cell cycle checkpoint for signal ends to be repaired prior to cell division, and 2) inducing survival of DN3 thymocytes while undergoing the G2/M cell cycle checkpoint. We will investigate whether: 1) activation of p38 MAPK by signal ends promotes nuclear accumulation of p38 MAPK through its association with NBS1 to induce a G2/M cell cycle checkpoint in DN3 thymocytes (Aim 1), p38 MAPK promotes survival in DN3 thymocytes while undergoing the G2/M cell cycle checkpoint through phosphorylation and inactivation of GSK3¿ (Aim 2), 3) activation of p38 MAPK and establishment of a G2/M cell cycle checkpoint is essential for repairing signal ends and preventing integration of signal joints into the genome (Aim 3).