Hypoxia inducible factor 2 (HIF-2) is a transcriptional activator implicated in the cellular response to hypoxia. Regulation of its inducible subunit, HIF-2α (also known as EPAS1), involves posttranslational modifications. Here, we demonstrate that casein kinase 1δ (CK1δ; also known as CSNK1D) phosphorylates HIF-2α at Ser383 and Thr528 in vitro. We found that disruption of these phosphorylation sites, and silencing or chemical inhibition of CK1δ, reduced the expression of HIF-2 target genes and the secretion of erythropoietin (EPO) in two hepatic cancer cell lines, Huh7 and HepG2, without affecting the levels of HIF-2α protein expression. Furthermore, when CK1δ-dependent phosphorylation of HIF-2α was inhibited, we observed substantial cytoplasmic mislocalization of HIF-2α, which was reversed upon the addition of the nuclear protein export inhibitor leptomycin B. Taken together, these data suggest that CK1δ enhances EPO secretion from liver cancer cells under hypoxia by modifying HIF-2α and promoting its nuclear accumulation. This modification represents a new mechanism of HIF-2 regulation that might allow HIF isoforms to undertake differing functions.

Our data suggest a possible role of the ET-1/ETBR axis in regulating the sensitivity of MM cells to BTZ. Thus, combining bortezomib with strategies to target the ET-1 axis could prove to be a novel promising therapeutic approach in MM.

Mitosis ensures genome integrity by mediating precise segregation of the duplicated genetic material. Segregation of subcellular organelles during mitosis also needs to be tightly coordinated in order to warrant their proper inheritance and cellular homeostasis. The inheritance of mitochondria, a powerhouse of the cell, is tightly regulated in order to meet the high energy demand to fuel the mitotic machinery. Mitochondria are highly dynamic organelles, which undergo events of fission, fusion and transport during different cell cycle stages. Importantly, during mitosis several kinases phosphorylate the key mitochondrial factors and drive fragmentation of mitochondria to allow for their efficient distribution and inheritance to two daughter cells. Recent evidence suggests that mitochondrial fission can also actively contribute to the regulation of mitotic progression. This review aims at summarizing established and emerging concepts about the complex regulatory networks which couple crucial mitotic factors and events to mitochondrial dynamics and which could be implicated in human disease.

Ubiquitylation is one of the most common post-translational modifications (PTMs) of proteins that frequently targets substrates for proteasomal degradation. However it can also result in non-proteolytic events which play important functions in cellular processes such as intracellular signaling, membrane trafficking, DNA repair and cell cycle. Emerging evidence demonstrates that dysfunction of non-proteolytic ubiquitylation is associated with the development of multiple human diseases. In this review, we summarize the current knowledge and the latest concepts on how non-proteolytic ubiquitylation pathways are involved in cellular signaling and in disease-mediating processes. Our review, may advance our understanding of the non-degradative ubiquitylation process.

Highlights d PKD and MFF drive mitotic mitochondrial fission and chromosome segregation d PKD but not AMPK directly phosphorylates MFF specifically during mitosis d PKD-phosphorylated MFF is required and sufficient for mitotic mitochondrial fission d PKD-phosphorylated MFF protects cells from mitotic checkpoint slippage

Ubiquitin Binding Protein 2-like (UBAP2L, also known as NICE-4) is a ubiquitin- and RNA-binding protein, highly conserved in metazoans. Despite its abundance, its functions have only recently started to be characterized. Several studies have demonstrated the crucial involvement of UBAP2L in various cellular processes such as cell cycle regulation, stem cell activity and stress-response signaling. In addition, UBAP2L has recently emerged as a master regulator of growth and proliferation in several human cancers, where it is suggested to display oncogenic properties. Given that this versatile protein is involved in the regulation of multiple and distinct cellular pathways, actively contributing to the maintenance of cell homeostasis and survival, UBAP2L might represent a good candidate for future therapeutic studies. In this review, we discuss the current knowledge and latest advances on elucidating UBAP2L cellular functions, with an aim to highlight the importance of targeting UBAP2L for future therapies.

The helicase XPD is known as a key subunit of the DNA repair/transcription factor TFIIH. However, here, we report that XPD, independently to other TFIIH subunits, can localize with the motor kinesin Eg5 to mitotic spindles and the midbodies of human cells. The XPD/Eg5 partnership is promoted upon phosphorylation of Eg5/T926 by the kinase CDK1, and conversely, it is reduced once Eg5/S1033 is phosphorylated by NEK6, a mitotic kinase that also targets XPD at T425. The phosphorylation of XPD does not affect its DNA repair and transcription functions, but it is required for Eg5 localization, checkpoint activation, and chromosome segregation in mitosis. In XPD-mutated cells derived from a patient with xeroderma pigmentosum, the phosphomimetic form XPD/T425D or even the nonphosphorylatable form Eg5/S1033A specifically restores mitotic chromosome segregation errors. These results thus highlight the phospho-dependent mitotic function of XPD and reveal how mitotic defects might contribute to XPD-related disorders.

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