Volume 15 Issue 1, January 2013

Muller and Vousden discuss the functional outcomes of mutant p53 in cancer and outline the mechanisms through which gain-of-function mutant p53 forms exert their oncogenic effects.

Genome sequencing and RNAi have been powerful allies in the quest to assign function to every gene. Systematic RNAi screens identify essential genes efficiently, but are less effective with pleiotropic or redundant genes. A common trick used by geneticists to overcome this problem is to screen for genetic interactors — mutations that enhance or suppress the phenotype of a starting mutation. Now, this classic approach has been combined with the versatility of RNAi to generate an expanded gene network for cell polarity.

Spindle orientation plays a pivotal role in tissue morphogenesis. An asymmetric anthrax receptor cap is revealed to promote activation of a formin to orient the spindle along the planar cell polarity (PCP) axis in zebrafish dorsal epiblast cells.

Primordial germ cell (PGC) development in the human fetus remains relatively uncharted. A new study suggests that epigenetic reprogramming and sex differentiation in human PGCs occur asynchronously over an extended time period. This finding raises questions and implications for in vitro PGC differentiation.

Mammary gland morphogenesis involves the polarization of epithelial cells and the formation of a lumen. Akhtar and Streuli demonstrate that β₁ integrin and the downstream kinase ILK at the basement membrane are required for polarization in this system, through orientation of microtubules and Golgi positioning.

The Wnt/planar cell polarity (Wnt/PCP) pathway orients cell division in various developmental contexts including zebrafish gastrulation. Gonzalez-Gaitan and colleagues reveal that, downstream of Wnt/PCP, the anthrax toxin receptor 2a interacts with actin to form a cortical actin cap in dorsal epiblast cells, and acts through RhoA and the formin zDia2 to orient the mitotic spindle.

Accurate chromosome segregation requires that sister-chromatid cohesion is resolved first at chromosome arms in prophase and then at centromeres in metaphase. In prophase, centromeric cohesion is protected by shugoshin and protein phosphase 2A (SGO1–PP2A). Yu and colleagues show that CDK1-mediated phosphorylation of SGO1 promotes SGO1–PP2A binding to cohesin, and dephosphorylation of the cohesion-promoting component sororin to prevent cohesin removal.

Robinson and colleagues perform a human-genome-wide siRNA screen to identify regulators of clathrin-coated vesicle formation. The knockdown phenotype of one of their hits, V-ATPase, is rescued by exogenous cholesterol, revealing an intriguing link between cholesterol and clathrin-coated vesicle formation.

An intriguing intersection between the AMPK and Hippo signalling pathways provides fresh insight into how nutrient availability regulates cell growth. Tapon and colleagues show that Drosophila salt-inducible kinases (Sik2/3), members of the AMPK family, phosphorylate the Hippo pathway protein Sav to attenuate Hippo signalling and promote Yki transcriptional activity.

The mTORC1 complex promotes protein translation and cell growth, whereas mTORC2 promotes survival. The Tel2 and Tt1 proteins belong to both complexes. Bassermann and colleagues demonstrate that following growth-factor deprivation, casein kinase 2 mediates phosphorylation of Tel2 and Tt1, specifically in the mTORC1 complex, to target them for degradation by the SCF^Fbxo9 ubiquitin ligase. This mechanism inactivates mTORC1 and activates mTORC2 and Akt signalling to promote survival of multiple myeloma cells.

To segregate chromosomes, spindle microtubules must attach to chromosomes through kinetochores, in a process involving several types of microtubule behaviour. Tolic-Norrelykke and colleagues find that fission yeast microtubules rapidly rotate around the spindle poles, and mathematical modelling confirms that this random microtubule movement facilitates kinetochore capture.

The Cdc2 (also called Cdk1) kinase is first activated at the centrosome to initiate mitosis in human cells. Hagan and colleagues demonstrate that in fission yeast, Cdc2 and Polo kinase activation at the spindle pole body remotely controls not only mitotic commitment but also ‘new end take off’, the initiation of bipolar growth in G2.

The amount of the BubR1 checkpoint protein declines with age in mouse models, suggesting that it has a role in ageing. Van Deursen and colleagues reveal that expressing a BubR1 transgene in mice reduces tumorigenesis and aneuploidy, and delays ageing-related phenotypes.

Cell polarity is important for the function of many animal cells, and several aspects of its establishment are conserved across species, from worm to human. Ahringer and colleagues have performed large-scale genetic interaction screens in Caenorhabditis elegans to identify a network of polarity regulators that includes genes not previously associated with polarity, such as the nuclear pore protein NPP-2.

Clark and colleagues have characterized the stages during which global epigenetic reprogramming occurs in human primordial germ cells, and delineate the appearance of these changes at 16 days of differentiation.