FEBS Press is pleased to welcome its fourth journal, Molecular Oncology, to this platform. Molecular Oncology is now fully Open Access and all content from the past 10 years is now available for all to read. The publication of high-quality journals by scientists for scientists is one the core objectives of The Federation of European Biochemical Societies (FEBS), with the revenue raised supporting fellowships, courses, congresses and other activities.
A circadian clock gene, PER2, activates HIF-1 as an effector molecule for recruitment of HIF-1α to promoter regions of its downstream genes
Harada and colleagues, The FEBS Journal
The hypoxia-inducible factor 1 (HIF-1α) is a transcription factor that mediates cellular responses to hypoxia. HIF-1α is known to be upregulated by a component of the circadian clock, the period clock 2 (PER2), but the underlying mechanism was unclear. Harada and colleagues now show that PER2 interacts with HIF-1α and facilitates its recruitment to a hypoxia-response element in the promoter of the vascular endothelial growth factor (VEGF). This PER2-mediated activation occurs in hypoxic conditions and depends on the hydroxylation status of N803 in HIF-1α.
Buckley and King, The FEBS Journal
Macropinocytosis is the non-specific uptake of extracellular fluid by cells such as macrophages and dendritic cells. It has recently been implicated in the pathogenesis of certain neurodegenerative diseases, atherosclerosis and cancer. In this State-of-the-Art Review, Buckley and King highlight the mechanisms underlying membrane rearrangements during macropinosome formation, the signalling cascades that regulate this process and the future directions in this fast-growing field.
Differential requirement for ATG2A domains for localization to autophagic membranes and lipid droplets
Mizushima, N. and colleagues, FEBS Letters
Autophagy initiates with formation of the phagophore, which engulfs cytoplasmic content to form the autophagosome. Autophagy-related (ATG) proteins, such as ATG2A, regulate the membrane dynamics of autophagosome formation. ATG2A localizes to phagophores and lipid droplets. Here, using truncation mutants, Mizushima and colleagues determine the domains of ATG2A that control subcellular localization and autophagosome formation.
Interaction between human angiogenin and the p53 TAD2 domain and its implication for inhibitor discovery
Jeon YH, Cheong HK and colleagues, FEBS Letters
Yeo et al. identify two positively-charged motifs on human Angiogenin that can potentially be targeted by small inhibitors to counteract the tumorigenic function of this protein at multiple levels. Angiogenin has been previously reported to bind to the p53 TAD2 domain and inhibit apoptosis. 31RRR33 and 50KRSIK54 are now shown to be involved in p53 binding. Of note, these motifs coincide with the heparin- and DNA-binding site on Angiogenin.
A uremic toxin (indoxyl sulfate) found in chronic kidney disease supresses bone formation and resorption
Inada and colleagues, FEBS Open Bio
Patients with chronic kidney disease (CKD) often present with bone turnover abnormalities, which has been associated with low serum levels of parathyroid hormone (PTH). Here, Inada and colleagues report that Indoxyl sulphate (IS), a uremic toxin known to accumulate in the blood of CKD patients, directly supresses osteoblast/osteoclast coupling and bone formation in vitro. This, combined with their previous findings that showed IS exacerbated low bone turnover induced by parathyroidectomy suggests that IS directly induces low bone turnover via the inhibition of bone formation using mechanisms separate from skeletal resistance to parathyroid hormone (PTH). This suggests IS initiates low-turnover bone disease in patients with CKD via a direct action upon both osteoclast precursors and osteoblasts to supress bone formation and resorption.
Hombach-Klonisch and colleagues, Molecular Oncology
Dovitinib (Dov), an FDA- approved oral drug, is able to cross the blood-brain barrier and has recently demonstrated promising efficacy in clinical trials for glioblastoma (GB) patients with recurrent disease. The Dov-mediated molecular mechanisms in GB cells remained unknown. Here, Hombach-Klonisch and colleagues show that Dov treatment attenuated the STAT3/LIN28/Let-7/HMGA2 regulatory axis in GB cells, and downregulated key base excision repair factors known to repair temozolomide (TMZ) induced DNA damage. Dual or sequential treatment with Dov and TMZ enhanced the efficacy of TMZ, reduced GB cell survival, growth, and self-renewal capacity and severely compromised the recovery of GB cells. Alternate administration of Dov and TMZ may improve therapeutic efficacy, especially in patients expected to exhibit increased TMZ resistance. These findings suggest ‘Dov priming’ is an encouraging novel therapeutic strategy to improve the efficacy of TMZ in patients with GB.
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