Articles in 2013

Sahai and colleagues report that YAP is required for the establishment and function of cancer-associated fibroblasts. They propose that matrix stiffening promotes Src-mediated activation of YAP in fibroblasts, which is necessary for the cancer-associated fibroblast phenotype and further promotes matrix stiffening in a positive feedback loop.

The protein kinase ULK1 regulates autophagy induction but its mode of action is poorly understood. Guan and colleagues show that following nutrient starvation, ULK1-mediated phosphorylation of Beclin-1 is required for the activation of VPS34 lipid kinase within the autophagy complex ATG1–VPS34–Beclin-1. They also find that during starvation, the inhibitory effect of mTOR on ULK1 is relieved to increase the phosphorylation of Beclin-1.

Centrosome amplification is often seen in cancer cells and may cause aneuploidy. Basto and colleagues unexpectedly find that centrosome amplification (induced by Plk4 overexpression) in the mouse central nervous system causes microcephaly due to depletion of the neural stem cell pool through aneuploidy and cell death.

Oligodendrocytes produce myelin in the central nervous system and can regenerate in adults. Brunet and colleagues show that inactivation of SIRT1 deacetylase increases the proliferation of oligodendrocyte progenitors partly by shifting other neural stem cells to this fate. Using genome-wide approaches, they delineate PDGFRα as a critical target of SIRT1 in its negative effects on oligodendrocyte lineage.

Axonemal microtubules are crosslinked to the surrounding plasma membrane at the ciliary base, in the transition zone. Tsou and colleagues have identified a centriole distal-end protein, CEP162, which mediates the association of transition zone components to axonemal microtubules.

Longmore and colleagues show that in cancer cells that have undergone epithelial-to-mesenchymal transition (EMT), activation of the collagen I receptor DDR2 results in ERK2-dependent maintenance of the protein levels and activity of the EMT inducer SNAIL1, thus facilitating cancer cell invasion and metastasis.

Adult mouse subependymal neural stem cells (aNSCs) give rise to neuronal and oligodendroglial progeny. Berninger and colleagues use continuous live imaging and single-cell tracking to demonstrate that single aNSCs isolated from the mouse brain generate exclusively either oligodendrocytes or neurons. They also show that Wnt activation stimulates oligodendrogenic progenitor proliferation without affecting neurogenic clones.

Using embryonic stem cells (ESCs) expressing controlled levels of Oct4 (a master transcription factor for pluripotency and reprogramming), Silva and colleagues show that although ESC levels of Oct4 are needed for pluripotency entry, Oct4 levels can decrease once pluripotency is established, without affecting self-renewal. However, ESC levels of Oct4 are required for differentiation to all lineages, as cells with low levels of Oct4 during differentiation remain in a naïve pluripotent state.

Brown adipose cells contribute to body temperature maintenance by converting lipids and glucose into heat, and can be found in white adipose tissue. Wolfrum and colleagues find a population of cells in white adipose tissue that can adopt brown or white characteristics in response to cold.

In the presence of stress stimuli, the endoplasmic reticulum either adapts the protein synthesis or triggers an apoptotic response, but the mechanisms underlying this decision are unknown. Kaufman and colleagues show that the ER stress response factors ATF4 and CHOP increase protein synthesis, which in turn induces oxidative stress and increased ATP consumption, leading to cell death during chronic ER stress.

During fasting, cellular lipophagy is activated and lipid stores are catabolized. O’Rourke and Ruvkun identify two metabolic transcriptional regulators, MXL-3 and HLH-30, which orchestrate the adaptive response to fasting by modulating the expression of lysosomal lipases and autophagy genes. In addition, they show that these regulators can influence C. elegans aging.

FOXO transcription factors confer stress resistance and longevity in several organisms. Ruvkun and colleagues demonstrate in Caenorhabditis elegans that DAF-16 (FOXO homologue) recruits the chromatin remodeller SWI/SNF to target genes. They show that SWI/SNF is required for DAF-16-mediated functions such as dauer formation, stress resistance and increasing longevity.

Ballabio and colleagues report that the transcription factor TFEB, which has a known role in autophagy, is induced by starvation and promotes transcription of PGC1α and PPARα. Intriguingly, targeted expression of TFEB in the liver blocks the development of metabolic syndrome in mouse models of obesity.

Notch signalling modulates fate decisions in stem and progenitor cells in various tissues. Artavanis-Tsakonas and colleagues use in vivo genetic labelling to uncover cell progenitors that are implicated in mammary gland branching and alveolar formation.

Phosphatidylinositol-3-OH kinase (PI(3)K) signalling regulates many cellular events such as cell growth and survival. Pagano and colleagues show that the E3 ligase SCF-FBXL2 promotes PI(3)K signalling and inhibits autophagy by targeting the free p85β subunit of the p110–p85 PI(3)K complex for degradation.

Internalized transmembrane proteins can be recycled to the plasma membrane by SNX27–retromer-mediated transport. Cullen and colleagues have done a global analysis of retromer-mediated transport by combining quantitative proteomics to delineate the SNX27 interactome and an analysis of the surface proteome of SNX27- or retromer-suppressed cells. They show that the SNX27–retromer complex recycles proteins involved in maintaining cellular nutrient homeostasis and is required to prevent lysosomal degradation of the recycling cargoes.

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 p150^Glued 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.

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.

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.