Department of Biochemistry and Molecular Biology, Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
J Biol Chem. 2011 Oct 21;286(42):36724-38. doi: 10.1074/jbc.M111.277673. Epub 2011 Aug 23.
Mammalian cells respond to protein or amino acid (AA) limitation by activating a number of signaling pathways, collectively referred to as the AA response (AAR), that modulate a range of cellular functions, including transcriptional induction of target genes. This study demonstrates that in hepatocellular carcinoma cells, expression of c-JUN, JUN-B, c-FOS, and FOS-B was induced by the AAR, whereas JUN-D, FRA-1, and FRA-2 were not. Of the four activated FOS/JUN members, c-JUN made the largest contribution to the induction of several known AAR target genes. For several human liver, prostate, and ovarian cell lines, the AAR-induced increase in c-JUN expression was greater in transformed cells compared with nontransformed counterparts, an effect independent of cell growth rate. Thus far, the best characterized AA-responsive genes are all transcriptionally activated by ATF4, but the AAR-dependent induction of c-JUN transcription was ATF4-independent. The increased expression of c-JUN was dependent on ATF2 and on activation of the MEK-ERK and JNK arms of the MAPK signaling pathways. Formation of c-JUN-ATF2-activated heterodimers was increased after AA limitation, and c-JUN or ATF2 knockdown suppressed the induction of c-JUN and other AAR target genes. AA deprivation triggers a feed-forward process that involves phosphorylation of existing c-JUN protein by JNK and subsequent auto-activation of the c-JUN gene by recruitment of c-JUN and ATF2 to two AP-1 sites within the proximal promoter. The results document the novel observation that AP-1 sequences within the c-JUN gene can function as transcriptional amino acid-response elements.
哺乳动物细胞通过激活多种信号通路来响应蛋白质或氨基酸（AA）的限制，这些信号通路统称为 AA 反应（AAR），它们调节多种细胞功能，包括目标基因的转录诱导。本研究表明，在肝癌细胞中，AAR 诱导 c-JUN、JUN-B、c-FOS 和 FOS-B 的表达，而 JUN-D、FRA-1 和 FRA-2 则不受影响。在四个激活的 FOS/JUN 成员中，c-JUN 对几个已知的 AAR 目标基因的诱导作用最大。对于几种人类肝脏、前列腺和卵巢细胞系，与非转化细胞相比，转化细胞中 AAR 诱导的 c-JUN 表达增加更大，这种效应独立于细胞生长速率。到目前为止，最好表征的 AA 反应基因都是通过 ATF4 转录激活的，但 c-JUN 转录的 AAR 依赖性诱导是 ATF4 非依赖性的。c-JUN 的表达增加依赖于 ATF2 和 MAPK 信号通路的 MEK-ERK 和 JNK 分支的激活。AA 限制后，c-JUN-ATF2 激活的异源二聚体的形成增加，而 c-JUN 或 ATF2 的敲低抑制了 c-JUN 和其他 AAR 目标基因的诱导。AA 剥夺触发了一个正反馈过程，涉及 JNK 对现有 c-JUN 蛋白的磷酸化，以及通过招募 c-JUN 和 ATF2 到近端启动子内的两个 AP-1 位点，对 c-JUN 基因的自身激活。这些结果记录了一个新的观察结果，即 c-JUN 基因内的 AP-1 序列可以作为转录氨基酸反应元件发挥作用。
