Articles in 2011

Peterson and colleagues find that the B9 complex localizes to the base of the primary cilia, where it functions as a ciliary diffusion barrier. Mutations in some B9 components are linked to human ciliopathies. The authors show that depleting components of the complex impairs primary cilia formation and inhibits the proper localization and function of signalling receptors in the cilia.

Bastiaens and colleagues find that PDEδ can solubilize Ras family small GTPases, resulting in their release from cellular membranes. This concentrates Ras proteins at specific subcellular locations, which promotes their eventual association with the plasma membrane and potentiates Ras-mediated signal transduction.

Ostrowski and colleagues identify a tumour-suppressive pathway in the tumour stroma. They show that PTEN loss in stromal fibroblasts downregulates miR-320, leading to the upregulation of the ETS2 transcription factor and the induction of a secretome that promotes tumour growth, invasion and angiogenesis.

Unrestrained Src signalling can be toxic for cancer cells. Wilkinson, Frame and colleagues show that active Src is sequestered in autophagosomes in cancer cells. Inhibition of autophagy induces cancer cell death.

The transcriptional role of c-Myc in maintaining tissue homeostasis is still unclear. Using mice conditionally expressing an activated form of c-Myc in the epidermis, and genome-wide approaches, Frye and colleagues show that c-Myc modulates the expression of the epidermal differentiation complex locus in the skin by displacing or recruiting specific transcriptional regulators. c-Myc activity is negatively regulated in vivo in this context by Sin3a.

Chromosomal microtubules participate in formation of kinetochore fibres by attaching their plus ends at kinetochores and focusing their minus ends at the spindle poles. Vernos and colleagues show that the centrosome-localized protein MCRS1 accumulates to chromosomal microtubule minus ends in a RanGTP-dependent manner to prevent microtubule depolymerization and to promote kinetochore-fibre stability and spindle assembly.

Wallerian degeneration occurs in axons following cutting or crush injuries; however, the molecular mechanisms that regulate this process remain elusive. Araki and colleagues find that the ubiquitin ligase ZNRF1 promotes Wallerian degeneration by ubiquitylating AKT, which leads to increased GSK3B activity and subsequent inhibition of the tubulin-binding protein CRMP2.

An epithelial cell can be engulfed by its neighbour through entosis, which frequently results in the death of the entosed cell. Overholtzer and colleagues show that the autophagy machinery is recruited to single-membrane entotic vacuoles and promotes their fusion with lysosomes. Single-membrane macrophage phagosomes containing apoptotic cells are also targeted for destruction by the autophagy pathway.

Spector and colleagues demonstrate that transcriptional activation after mitosis occurs with much faster kinetics than in interphase. Increased acetylation of lysine 5 on histone H4 is maintained during mitosis to recruit bromodomain protein 4, which then facilitates chromatin decompaction for transcriptional reactivation.

The ubiquitin–proteasome system clears misfolded proteins to maintain cellular homeostasis. Mayor and colleagues identify the ubiquitin ligase Hul5 as a critical component of the heat-shock response and show that it selectively targets misfolded cytosolic proteins for degradation.

In humans, mutations in the DNA-damage-response modulator MCPH1 are associated with defective neural development. Wang and colleagues show that mutations in mouse MCPH1 result in microcephaly through the delocalization of Chk1 from centrosomes, causing the uncoupling of mitosis and centrosome duplication, and resulting in spindle misorientation and a switch in the fate of neural stem cell daughters.

Non-enveloped viruses such as SV40 are transported from the extracellular space into the host cell nucleus through a pathway involving endocytosis, trafficking to the endoplasmic reticulum (ER) lumen, transport across the ER membrane to the cytoplasm, and subsequent nuclear import. Helenius and colleagues provide insight into how SV40 escapes from the ER by showing that viral proteins interact with components of the host ER-associated degradation machinery (ERAD). These interactions are crucial for translocation of SV40 into the cytoplasm and infectivity.

Ivaska and colleagues identify SHARPIN as an inhibitor of integrin activity in an RNAi screen for integrin regulators. They show that SHARPIN acts by binding to the cytoplasmic domain of integrin α-subunits and reduces the recruitment of talin and kindlin to the β-subunits.

The spindle assembly checkpoint halts cell-cycle progression in the presence of unattached kinetochores by preventing activation of APC/C. Pines and colleagues find that APC15 has a critical role in regulating APC/C activation by promoting release of the inhibitory MCC complex from APC/C once the spindle assembly checkpoint is satisfied.

ATP production by mitochondria requires the efficient flow of protons through the F₁F_O ATP-synthase complex. Jonas and colleagues show that Bcl-xL interacts with the F₁F_O complex in the mitochondrial matrix and increases the efficiency of this enzyme by decreasing proton leak.

Cell polarity is critically important for organogenesis. Using a series of RNA-interference-based screens, Göbel and colleagues reveal the role of the glycosphingolipid glucosylceramide (GlcCer) in determining apicobasal polarity and maintaining the organization of the intestinal lumen in the developing worm.

Notch and VEGF signalling controls the specification of endothelial cells to tip and stalk cells during angiogenesis sprouting. Alitalo and colleagues show that macrophage-derived VEGF-C activates VEGFR2 to contribute to the conversion of endothelial cells from a tip- to a stalk-cell fate when two sprouts fuse to ensure vessel growth and branching.

Doxsey and colleagues report that midbodies accumulate in stem cells, including induced pluripotent stem cells and potential cancer-initiating cells. Loss of midbodies accompanies stem-cell differentiation and is mediated through binding of the autophagy receptor NBR1 to the midbody protein CEP55. Downregulation of NBR1 is associated with enrichment of midbodies, enhanced reprogramming and increased tumorigenicity in cancer cells.

Drosophila L(3)mbt mutant brains are shown to develop brain tumours owing to derepression of the target genes of the Salvador–Warts–Hippo pathway, resulting in overproliferation of neuroepithelial cells in the optic lobes. L(3)mbt is found to act in this process by binding to insulator elements at the promoters of these target genes.

Cancer stem cells (CSCs) have been linked to the maintenance and progression of several tumours, but the properties of human CSCs are not well known. Reprogramming of human somatic cells during neoplastic in vitro transformation is shown to confer the properties of stem cells to primary differentiated fibroblasts. The cells that give rise to tumours in this case express the SSEA-1 antigen.