Volume 15 Issue 6, June 2013

Pencheva and Tavazoie discuss the recent advances in understanding how microRNAs control metastatic progression in cancer.

The metabolic activity of a cell or organism must be regulated by nutrient availability. Dibble and Manning discuss how the activity of the mTORC1 complex, a master regulator of metabolism, is able to respond to the nutrient environment.

Autophagy contributes to lipid catabolism through direct mobilization and breakdown of cellular lipid stores. Two recent studies reveal the regulatory mechanisms activated by cells during starvation to ensure that the cellular compartments involved in autophagic lipid catabolism are ready to receive, process and use these lipids. The regulators represent attractive therapeutic targets to help fight lipid-excess-associated diseases.

Identification and characterization of a third type of adipocyte known as brite (brown-in-white) adipocytes has drawn considerable attention, as these cells are thought to regulate energy expenditure and may help combat obesity. Remarkably, white adipocytes can adopt the characteristics of brite adipocytes following cold stimulation, and this process is reversible in vivo.

Cancer-associated fibroblasts (CAFs) may contribute to tissue tension and cancer progression by increasing extracellular matrix (ECM) deposition and remodelling. However, how CAFs become activated and their roles in tumour mechanics have remained unclear. YAP is now identified as a tension-stimulated CAF activator that promotes malignancy through a mechanically reinforced feed-forward loop.

Although myelination largely occurs during early postnatal life, myelinating oligodendrocytes are still generated in the adult brain. Myelin turnover in the adult is necessary for proper neuronal function and is gravely compromised in myelin disorders. The lineage relationship between adult neural stem cells and adult-born oligodendrocytes has been clarified, highlighting molecular pathways that could potentially be targeted to favour de novo myelination in pathological situations.

How different integrin receptors for the same extracellular ligand transduce distinct cellular responses is unclear. The characterization of the class-specific adhesomes of β₁ and α_V integrins now shows that whereas α_V integrins promote unbranched actin polymerization, β₁ integrins induce myosin-II-dependent contractility, and both integrin subtypes synergistically mediate rigidity sensing.

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.

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.

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.

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.

Faessler and colleagues analyse the distinct properties of β₁ and α_v integrin subclasses, and provide insight into the different protein compositions, signalling activities and contributions to rigidity sensing of adhesion sites anchored by each integrin subtype.

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.

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.

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.

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.

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.

Howard and colleagues demonstrate that the XMAP215 and EB1 microtubule plus-end binding proteins synergistically promote microtubule growth in vitro, at rates comparable to those measured in cells.

For double-strand breaks to be repaired by homologous recombination, the homologous template must be in the nuclear space. By elegant genetic manipulation of yeast chromosomes, Kupiec and colleagues show that nuclear organization influences repair efficiency.

Human embryonic stem cells contain 5-hydroxymethylcytosine (5hmC) generated by the TET enzyme. Jin and colleagues show that TET1 increases 5hmC levels during reprogramming to human inducible pluripotent stem cells, and although this change is critical for optimal epigenetic reprogramming, it does not compromise primed pluripotency.