During hypoxia, a cellular adaptive response activates hypoxia‐inducible factors (HIFs; HIF‐1 and HIF‐2) that respond to low tissue‐oxygen levels and induce the expression of a number of genes that promote angiogenesis, energy metabolism, and cell survival. HIF‐1 and HIF‐2 regulate endothelial cell (EC) adaptation by activating genesignaling cascades that promote endothelial migration, growth, and differentiation. An HIF‐1 to HIF‐2 transition or switch governs this process from acute to prolonged hypoxia. In the present study, we evaluated the mechanisms governing the HIF switch in 10 different primary human ECs from different vascular beds during the early stages of hypoxia. The studies demonstrate that the switch from HIF‐1 to HIF‐2 constitutes a universal mechanism of cellular adaptation to hypoxic stress and that HIF1A and HIF2A mRNA stability differences contribute to HIF switch. Furthermore, using 4 genome‐wide mRNA expression arrays of HUVECs during normoxia and after 2, 8, and 16 h of hypoxia, we show using bioinformatics analyses that, although a number of genes appeared to be regulated exclusively by HIF‐1 or HIF‐2, the largest number of genes appeared to be regulated by both.—Bartoszewski, R., Moszynska, A., Serocki, M., Cabaj, A., Polten, A., Ochocka, R., Dell'Italia, L., Bartoszewska, S., Króliczewski, J., Dabrowski, M., Collawn, J. F. Primary endothelial cell–specific regulation of hypoxia‐inducible factor (HIF)‐1 and HIF‐2 and their target gene expression profiles during hypoxia. FASEB J. 33, 7929–7941 (2019). http://www.fasebj.org

Inhibition of oncogenic transcriptional programs is a promising therapeutic strategy. A substituted tricyclic benzimidazole, SEL120-34A, is a novel inhibitor of Cyclin-dependent kinase 8 (CDK8), which regulates transcription by associating with the Mediator complex. X-ray crystallography has shown SEL120-34A to be a type I inhibitor forming halogen bonds with the protein's hinge region and hydrophobic complementarities within its front pocket. SEL120-34A inhibits phosphorylation of STAT1 S727 and STAT5 S726 in cancer cells in vitro. Consistently, regulation of STATs- and NUP98-HOXA9- dependent transcription has been observed as a dominant mechanism of action in vivo. Treatment with the compound resulted in a differential efficacy on AML cells with elevated STAT5 S726 levels and stem cell characteristics. In contrast, resistant cells were negative for activated STAT5 and revealed lineage commitment. In vivo efficacy in xenotransplanted AML models correlated with significant repression of STAT5 S726. Favorable pharmacokinetics, confirmed safety and in vivo efficacy provide a rationale for the further clinical development of SEL120-34A as a personalized therapeutic approach in AML.

During endoplasmic reticulum (ER) stress conditions, an adaptive signaling network termed the unfolded protein response (UPR) is activated. The UPR's function is to increase ER protein‐folding capacity in order to attenuate ER stress, restore ER homeostasis, and, most importantly, promote cell survival. X‐box–binding protein 1 (XBP1) is one component of the UPR and is a proadaptive transcription factor that is subject to transcriptional, post‐transcriptional, and post‐translational control. In the present study, we identified a post‐transcriptional mechanism mediated by miR‐34c‐5p that governs the expression of both the spliced (active) and unspliced (latent) forms of XBP1 mRNAs. We showed that miR‐34c‐5p directly attenuates spliced XBP1 (XBP1s) mRNA levels during ER stress and thus regulates the proadaptive component of the UPR that is mediated by XBP1s without interfering with the induction of apoptotic responses.—Bartoszewska, S., Cabaj, A., Dabrowski, M., Collawn, J. F., Bartoszewski, R. miR‐34c‐5p modulates X‐box‐binding protein 1 (XBP1) expression during the adaptive phase of the unfolded protein response. FASEB J. 33, 11541–11554 (2019). http://www.fasebj.org