Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Exp Med. 2012 Jan 16;209(1):11-7. doi: 10.1084/jem.20112078. Epub 2011 Dec 26.
Interleukin 7 (IL-7) promotes pre-B cell survival and proliferation by activating the Pim1 and Akt kinases. These signals must be attenuated to induce G1 cell cycle arrest and expression of the RAG endonuclease, which are both required for IgL chain gene rearrangement. As lost IL-7 signals would limit pre-B cell survival, how cells survive during IgL chain gene rearrangement remains unclear. We show that RAG-induced DNA double-strand breaks (DSBs) generated during IgL chain gene assembly paradoxically promote pre-B cell survival. This occurs through the ATM-dependent induction of Pim2 kinase expression. Similar to Pim1, Pim2 phosphorylates BAD, which antagonizes the pro-apoptotic function of BAX. However, unlike IL-7 induction of Pim1, RAG DSB-mediated induction of Pim2 does not drive proliferation. Rather, Pim2 has antiproliferative functions that prevent the transit of pre-B cells harboring RAG DSBs from G1 into S phase, where these DNA breaks could be aberrantly repaired. Thus, signals from IL-7 and RAG DSBs activate distinct Pim kinase family members that have context-dependent activities in regulating pre-B cell proliferation and survival.
白细胞介素 7（IL-7）通过激活 Pim1 和 Akt 激酶促进前 B 细胞的存活和增殖。这些信号必须减弱，以诱导 G1 细胞周期阻滞和 RAG 内切酶的表达，这两者都是 IgL 链基因重排所必需的。由于丢失的 IL-7 信号会限制前 B 细胞的存活，因此细胞在 IgL 链基因重排期间如何存活仍不清楚。我们表明，在 IgL 链基因组装过程中产生的 RAG 诱导的 DNA 双链断裂（DSB）出人意料地促进了前 B 细胞的存活。这是通过 ATM 依赖性诱导 Pim2 激酶表达来实现的。与 Pim1 相似，Pim2 磷酸化 BAD，从而拮抗 BAX 的促凋亡功能。然而，与 IL-7 诱导的 Pim1 不同，RAG DSB 介导的 Pim2 诱导不驱动增殖。相反，Pim2 具有抗增殖功能，可防止携带 RAG DSB 的前 B 细胞从 G1 进入 S 期，在此期间这些 DNA 断裂可能会异常修复。因此，来自 IL-7 和 RAG DSB 的信号激活了不同的 Pim 激酶家族成员，这些成员在调节前 B 细胞增殖和存活方面具有上下文相关的活性。
