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Cell biologists must decide whether to embrace the maturing field of systems biology. We argue that a fusion of the two is urgently needed to strengthen both fields.
Epithelial cells have an apical–basolateral axis of polarity, which is required for epithelial functions including barrier formation, vectorial ion transport and sensory perception. Here we review what is known about the sorting signals, machineries and pathways that maintain this asymmetry, and how polarity proteins interface with membrane-trafficking pathways to generate membrane domains de novo.It is becoming apparent that membrane traffic does not simply reinforce polarity, but is critical for the generation of cortical epithelial cell asymmetry.
Regulation of organ size is achieved through the action of the mTOR and Hippo signalling pathways, which control cell proliferation and cell growth in response to extracellular cues. A link between these pathways is revealed by the finding that YAP downregulates PTEN to promote cell growth and tissue hyperplasia.
Basal cell carcinoma has been shown to originate from activation of hedgehog signalling in interfollicular epidermal progenitor cells. Analyses of the early steps of basal cell carcinoma formation show that this process requires reprogramming of interfolliclular epidermal cells to an embryonic hair follicle progenitor-like fate, with concomitant Wnt pathway activation.
Brown adipose tissue is intensively researched owing to its role in regulating energy and glucose homeostasis. Its differentiation is controlled through adrenergic-dependent regulation of the transcriptional co-regulator Prdm16. Adrenergic stimulation inhibits expression of miR-133a/b in a Mef2c-dependent manner to abrogate post-transcriptional silencing of Prdm16.
Rinkevich, Weissman and colleagues show that mesothelin-expressing cells from the mesothelium, an epithelial monolayer covering vertebrate cavities and internal organs, generate the fibroblasts and smooth muscle cells (FSMCs) essential for the development of internal organs. Using a genetic lineage tracing approach, they find that these cells participate in generating FSMCs and vasculature, with minimal contributions from neural crest or circulating cells.
The peripheral actin cortex in cells is essential for secretory vesicle exocytosis, but also acts as a barrier for vesicle release. Wollman and Meyer report that antigen activation triggers cyclical waves of Ca2+ and PtdIns(4,5)P2 that promote N-WASP-mediated oscillations in F-actin polymerization. These permit secretion when F-actin levels are low, but impede exocytosis when F-actin levels are high.
Both telomerase activity and NF-κB-driven inflammation occur in tumours, and NF-κB is known to upregulate telomerase levels. Tergaonkar and colleagues now find evidence for a reciprocal direct regulation of NF-κB-dependent gene transcription by telomerase, through an interaction between telomerase and the NF-κB p65 subunit.
Blanpain and colleagues use mouse models of activated Hedgehog signalling to analyse the temporal gene expression changes involved in basal cell carcinoma initiation. They show that tumour initiation involves activation of the Wnt pathway and reprogramming of the adult interfollicular epidermis tumour-initiating cells into a cell fate resembling that of embryonic hair follicle progenitor cells.
Lu and colleagues delineate a pathway through which the PKM2 enzyme promotes aerobic glycolysis, known as the Warburg effect, in cancer cells. They show that EGFR-activated ERK phosphorylates PKM2, leading to its accumulation in the nucleus. Nuclear PKM2 subsequently promotes the c-Myc-dependent upregulation of genes involved in the Warburg effect, resulting in tumour growth.
Patterning of Drosophila embryos involves the localization of RNAs to specific places in the oocytes before fertilization. Although both gurken (grk) and bicoid (bcd) mRNA localize to the dorsoanterior of the oocyte, only grk mRNA is translated at this stage. Davis and colleagues find that grk mRNA co-localizes with proteins involved in translation at the periphery of P bodies whereas bcd is enriched into their central region—which the authors show is devoid of ribosomes—where it is translationally repressed.
Voinnet and colleagues show that autophagy targets RNAi components DICER and AGO2 for degradation when they are not bound to miRNA. The autophagy receptor NDP52 is required for this homeostatic regulation of the RNAi machinery. The authors also found that autophagy influences the post-translational regulation of DICER mRNA.
Guan and colleagues report that the Hippo pathway effector YAP regulates PI(3)K–mTOR signalling. YAP induces expression of the microRNA miR-29 to block PTEN expression, activating the PI(3)K pathway. Hippo and PI(3)K pathways thus converge to regulate cell growth and proliferation.
Brown adipose tissue generates heat on exposure to cold temperatures. Stoffel and colleagues identify a cold-regulated pathway that increases levels of the transcriptional regulator Prdm16 to promote brown adipogenesis.
The mitochondrial calcium uniporter (MCU) mediates calcium uptake by mitochondria and thus regulates cellular bioenergetics, but how MCU activity is modulated is not fully understood. Madesh, Foskett and colleagues report that the integral mitochondrial membrane protein MCUR1 (mitochondrial calcium uniporter regulator 1) binds to the MCU and promotes MCU-dependent calcium uptake to control ATP production and autophagy.
