Arabidopsis (Arabidopsis thaliana) WRKY33 is a key transcription factor in pathogen-induced defense signaling, but its function in abiotic stresses remains largely unclear. In this study, we report on the use of a rev...Arabidopsis (Arabidopsis thaliana) WRKY33 is a key transcription factor in pathogen-induced defense signaling, but its function in abiotic stresses remains largely unclear. In this study, we report on the use of a reverse-genetic approach, as well as a yeast (Saccharomyces cerevisiae) expression system, to determine the role of WRKY33 in drought. A T-DNA insertion deletion mutant of WRKY33 is more sensitive to dehydration. Through genome-wide screening the target genes of WRKY33 in yeast, we identified 23 candidate genes including a drought tolerance gene CesA8. Further results revealed that WRKY33 repressed CesA8 expression through binding to the W-box elements of CesA8 distal promoter region and probably interacting with the transcriptional activator of CesA8, MYB46. These findings revealed the primary molecular mechanism underlying the function of WRKY33 in response to展开更多
KRAS-PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here...KRAS-PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36 l(KD= 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS-PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36 l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft(PDX) models. It represents a promising lead compound for investigating the druggability of KRAS-PDEδ interaction.展开更多
基金Financial supports for this work, are provided by the National Natural Science Foundation of China （NSFC） ＆ Shenhua Group Corporation Limited key support project of the coal joint fund （U1361203） and NSFC under Grant No. 41501562. Thanks are also due to some participants for rendering assistant cooperation during studies.
文摘Arabidopsis (Arabidopsis thaliana) WRKY33 is a key transcription factor in pathogen-induced defense signaling, but its function in abiotic stresses remains largely unclear. In this study, we report on the use of a reverse-genetic approach, as well as a yeast (Saccharomyces cerevisiae) expression system, to determine the role of WRKY33 in drought. A T-DNA insertion deletion mutant of WRKY33 is more sensitive to dehydration. Through genome-wide screening the target genes of WRKY33 in yeast, we identified 23 candidate genes including a drought tolerance gene CesA8. Further results revealed that WRKY33 repressed CesA8 expression through binding to the W-box elements of CesA8 distal promoter region and probably interacting with the transcriptional activator of CesA8, MYB46. These findings revealed the primary molecular mechanism underlying the function of WRKY33 in response to
基金supported by the National Key R&D Program of China(Grant No.2020YFA0509100)the National Natural Science Foundation of China(Grants 21738002,82030105,81725020 and 81903436)。
文摘KRAS-PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36 l(KD= 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS-PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36 l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft(PDX) models. It represents a promising lead compound for investigating the druggability of KRAS-PDEδ interaction.
