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Cancer stem cells (CSCs) have been proposed as the driving force of tumorigenesis and the seeds of metastases. However, their existence and role remain a topic of intense debate. Recently, the identification of CSCs in endogenously developing mouse tumours has provided further support for this concept. Here I discuss the challenges in identifying CSCs, their dependency on a supportive niche and their role in metastasis, and propose that stemness is a flexible — rather than fixed — quality of tumour cells that can be lost and gained.
How application of force affects actin remodelling during mechanotransduction has remained unclear. Mechanical manipulation of the cell cortex is now shown to trigger actin monomer release from filaments, which in turn activates formin-dependent actin filament elongation. This force-sensitive actin polymerization does not require GTPases or membrane receptors, but it involves actin itself.
To ensure proper attachment of all chromosomes to the spindle, PLK1 has to associate with kinetochores during prometaphase and must be released from these sites before sister chromatid separation can begin. The monoubiquitylation of PLK1 by the ubiquitin ligase CUL3–KLHL22 is now identified as a critical step in promoting the release of PLK1 from kinetochores, pushing non-proteolytic ubiquitylation into the limelight of cell division research.
The recruitment of the silencing complex Polycomb group (PcG) to its target sites in mammalian cells has remained elusive. A prevalent model proposes that the PRC1 component is recruited through recognition of methylated H3K27 found at target sites occupied by the PRC2 component. However, mounting evidence suggests that PRC2-independent mechanisms of PRC1 recruitment exist. Three studies describe that the histone demethylase Kdm2b binds to unmethylated CpG islands and recruits a subset of PRC1 complexes to chromatin in pluripotent stem cells.
Self-renewal and differentiation of adult stem cells ensures tissue homeostasis. De Haan and colleagues find that the chromatin-associated polycomb protein Cbx7 ensures self-renewal of haematopoietic stem cells (HSCs), whereas other polycomb proteins, such as Cbx8, induce differentiation. They find that although genes targeted by Cbx8 are highly expressed in HSCs and repressed in progenitors, Cbx7 target genes have the opposite expression pattern.
Gottgens and colleagues have analysed the expression of 18 haematopoietic factors in single primary blood and progenitor cells from mouse bone marrow. They delineate distinct states of expression for these transcription factors and identify regulatory relationships between the key factors Gata2, Gfi1 and Gfi2.
How polycomb group proteins are recruited to lineage specific genes to repress their expression in mouse embryonic stem cells has been unclear. Zhang and colleagues show that the histone lysine demethylase Kdm2b recruits Ring1 of the PRC1 complex to a subset of these targets, through a non-catalytic domain. The expression of Kdm2 is also shown to be regulated by the pluripotency factors Oct4 and Sox2.
How the characteristic quiescent status of adult HSCs is maintained is not well understood. Tenen and colleagues show that the transcription factor C/EBP is required to maintain a low proliferation rate in adult HSCs, partly through N-Myc repression.
Watanabe and colleagues show that an increase in cytosolic G-actin levels following mechanical stress promotes Ca2+- and kinase-signalling-independent nucleation of actin filaments by formins.
mTOR inhibition induces autophage-mediated degradation but few mTOR targets in the process have been identified so far. Cecconi and colleagues show that mTOR inhibits the autophagy regulator AMBRA1 by phosphorylation. Following autophagy induction, AMBRA1 is dephosphorylated and interacts with the E3 ligase TRAF6 to stabilize and activate ULK1 (a kinase required for autophagy) through its ubiquitylation.
How the interaction between molecular motors and cargoes is regulated is not well understood. Liu and colleagues show that phosphatidylinositol-4-phosphate (PtdIns(4)P) dissociates the retromer component sorting nexin SNX6 from the p150Glued subunit of dynactin on retrograde transport vesicles docking at the trans-Golgi network. PtdIns(4)P is also shown to modulate the association of SNX4 and dynein on retrograde vesicles en route to the endocytic pathway.
The dynamic localization of PLK1 to kinetochores is required for faithful chromosome segregation. Peter, Sumara and colleagues demonstrate that a KHL22-containing E3 ligase mediates degradation-independent removal of PLK1 from kinetochores to ensure satisfaction of the spindle assembly checkpoint and proper mitotic progression.
