2020年9月15日 · To explore the potential mechanisms involved, we performed time-course drug treatment experiments on the parental MCF-7 and drug resistant MCF-7EpiR and MCF-7Tax R breast cancer cells and identified GCN2 (eIF2AK4) as a molecule that can potentially cooperate with PERK to regulate FOXO3 via JNK and AKT to modulate drug response.

We incubated recombinant GCN2 with uncharged tRNAs, neratinib, and a desthiobiotin-ATP probe, which biotinylates GCN2 when ATP has access to the kinase domain and then performed avidin capture of biotinylated GCN2.

Our results demonstrate that PERK and GCN2 function to cooperatively regulate eIF2α phosphorylation and cyclin D1 translation after UPR activation. Integral membrane proteins and secreted proteins are synthesized, folded, and posttranslationally modified in …

2008年12月8日 · GCN2 was activated by deprivation of the essential amino acid Met, and PERK was activated with 2,5-di-tert-butylhydroquinone (tBuHQ), a selective inhibitor of ATP-dependent microsomal Ca 2+ sequestration and activator of ER stress (32, 51). Overall, the results support the hypothesis, i.e., activation of GCN2 resulted in altered translation of ...

2019年1月9日 · GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic...

内质网（ER）应激调节剂PERK（eIF2AK3）的药物抑制剂已在联合疗法中显示出抗癌活性，但其作为单一药物的有效性受到限制，表明存在可能的代偿性细胞应答。 为了探索涉及的潜在机制，我们对父母MCF-7和耐药MCF-7Epi R 和MCF-7Tax R 进行了时程药物治疗实验 乳腺癌细胞，并确定GCN2（eIF2AK4）是一种分子，可以与PERK协同通过JNK和AKT调节FOXO3，从而调节药物反应。 一致地，GCN2敲低严重损害了亲本和耐药MCF-7细胞的克隆存活，并使它们对表柔比星 …

2023年10月9日 · Previous studies have shown that GCN2 is a viable cancer target when amino acid stress is induced by inhibiting an additional target. In this light, we screened numerous drugs for their potential to synergize with the GCN2 inhibitor TAP20. The drug sensitivity of six cancer cell lines to a panel of 25 compounds was assessed.

2020年9月15日 · Together these results demonstrate that GCN2 cooperates with PERK through the JNK-FOXO3 axis in a reciprocal negative feedback loop to mediate cancer chemotherapeutic drug response and clonal survival, advocating the potential of targeting GCN2 as a therapeutic strategy for treating cancer and for overcoming drug resistance.

此步骤必须受到密切调控，不同家族的 4 种应激激活的激酶 — pkr (dsrna)、perk（er 应激）、gcn2（氨基酸饥饿）和 hri（血红素不足）— 对 eif2α 的磷酸化后， eif2 可作为显性失活复合体隔绝 eif2b ，从而阻断核苷酸交换。

2021年12月23日 · A genome-wide CRISPR screen revealed that loss of general control nonderepressible 2 (GCN2) kinase increases cellular resistance to the pan-ErbB inhibitor neratinib with neratinib directly...