Letters in 2011

The signalling pathway by which ER damage triggers apoptosis remains unclear. Oakes and colleagues identify CT10-regulated kinase (CRK) as a pro-apoptotic protein induced by ER stress. Such stress leads to the accumulation of cleaved CRK fragments at mitochondria, sensitizing them to cytochrome c release in a cell-free system.

Wnt signalling regulates development and differentiation through both canonical and non-canonical pathways. Rudnicki and colleagues find that Wnt7a–Fzd7 activates Gα_s to promote Akt/mTOR pathway activation, and show that this non-canonical Wnt signalling pathway elicits myofibre hypertrophy in vivo.

Jürgens and colleagues show that the ARF GEFs GNOM and GNL2 have essential roles in polarized cell growth of root hairs and pollen, respectively. Their findings support an important function for endosomal recycling, rather than polarized secretion, in the targeted delivery of proteins necessary for polar tip growth.

p53 activates Puma-dependent apoptosis and p21-mediated cell-cycle arrest in response to DNA damage. Rudolph and colleagues show that stem-cell functionality in telomerase-deficient mice is improved by the deletion of Puma. Unexpectedly, the accumulation of progenitor cells with damaged short-telomere DNA is not seen in telomerase- and Puma-deficient animals, as p21-mediated cell-cycle arrest is activated to limit the expansion of these cells.

Caspase 8 is known to suppress necroptosis, but its relevant target protein was unknown. Ting and colleagues show that caspase 8 cleaves the deubiquitylase CYLD to inhibit necroptosis and promote cell survival.

Somatic reprogramming efficiency by expression of defined transcription factors can be enhanced by deletion of p53. He and colleagues found that the microRNA miR-34, which is induced by p53 during reprogramming, inhibits reprogramming, partly by direct repression of pluripotency factors. Deletion of Mir34 from mice increases reprogramming efficiency and kinetics without affecting self-renewal and differentiation.

The MYC proto-oncogene modulates transcription through binding to E-boxes. Di Croce and colleagues find that PAK-2-mediated phosphorylation confers a tumour-suppressive function to MYC, in which MYC cooperates with differentiation signals to positively modulate the transcription of genes targeted by retinoic acid, independently of E-boxes.

Aragón and colleagues show that the phosphatase Cdc14 acts on the CDT subunit of RNA polymerase II to silence transcription of repetitive regions of the yeast genome. At telomeres this event promotes condensin loading and mitotic segregation.

The p97 AAA+ ATPase (also known as VCP) functions in various ubiquitin-regulated processes. Ramadan and colleagues now find that p97 is recruited to sites of DNA damage by Lys-48-linked ubiquitin chains, which are formed in a process mediated by RNF8. p97 then removes Lys-48–ubiquitin conjugates and promotes recruitment of DNA-repair factors.

In mammalian cells, long-range vesicular transport is thought to occur via microtubule tracks. However, Schuh reports the existence of an actin-based pathway for long-range trafficking in mouse oocytes by showing that Rab11a-positive vesicles are decorated with actin-nucleating formin proteins. She finds that these proteins assemble actin networks that guide vesicles to the cell surface.

PAR polarity proteins are asymmetrically localized at the cortex of Caenorhabditis elegans zygotes. Seydoux and colleagues show that aPKC-mediated phosphorylation of PAR-2, which inhibits recruitment of PAR-2 to the cortex, is directly inhibited by microtubules emanating from the sperm-donated centrosomes. This protection allows PAR-2, and subsequently the PAR-1 kinase to access the cortex nearby the sperm, thus defining the posterior of the embryo. PAR-1 in turn phosphorylates PAR-3 to induce dissociation of PAR-3–aPKC from the posterior.

In yeast, polarized localization of Cdc42 is essential for budding and mating, but how polarity is attained has been elusive. Grinstein and colleagues show that phosphatidylserine accumulates in a polar fashion in yeast, and is required for the proper localization of Cdc42.

In the TGFβ pathway, receptor-activated SMADs (R-SMADs) associate with SMAD4 to regulate transcription. Piccolo and colleagues reveal that the deubiquitylase USP15 is required for TGFβ responses by reversing R-SMAD ubiquitylation and thereby promoting the retention of the SMAD complex at promoters.

Overlapping antiparallel microtubules are important in cellular structures such as the mitotic spindle. Diez and colleagues use an in vitro system and mathematical modelling to show that the formation of stable overlaps involves a motor such as kinesin-14, which slides microtubules apart, and a passive microtubule crosslinker, Ase1, which accumulates at microtubule overlapping regions and slows microtubule sliding to prevent their separation.

The microtubules that attach kinetochores to chromosomes (K-fibres) are stabilized in prometaphase to allow for accurate chromosome segregation. Kapoor and colleagues find that the B56-PP2A phosphatase stabilizes K-fibres potentially by counteracting the phosphorylation of kinetochore substrates that is mediated by Aurora B and Plk1.

Mammalian oocyte maturation involves two asymmetric meiotic divisions that require the positioning of the meiotic spindle near the cortical area from which the extrusion of the polar bodies occurs. Li and colleagues show that the nucleating activity of the Arp2/3 complex, localized at the cortical actin cap, induces actin-filament flow away from the complex, creating a cytoplasmic streaming that pushes the spindle towards the cortex.

Franzoso and colleagues show that NF-κB protects cells from nutrient-starvation-induced necrosis by upregulating mitochondrial respiration through increased p53-dependent expression of the SCO2 enzyme. Conversely, inhibition of NF-κB results in increased aerobic glycolysis, known as the Warburg effect, thus promoting oncogenic transformation, and affects metabolic adaptation during tumorigenesis in vivo.

The LIN-5/NuMA pathway is needed to correctly position the mitotic spindle for asymmetric division. Now van den Heuvel and colleagues find that polarity kinase aPKC–PKC-3 phosphorylates LIN-5 to direct the localization of the spindle in the early embryos of Caenorhabditis elegans.

Unpaired morphogen specifies migratory border-cell migration in a STAT-dependent manner, so that cells with low STAT signalling do not migrate. In a feedback loop, miR-279 generates a cell-fate threshold in STAT signalling in response to the Upd gradient to prevent inappropriate migration.

The E3 ligase RNF8 is recruited to double-strand breaks in DNA to promote repair. Jacobs and colleagues discovered that RNF8 also goes to unprotected telomeres, where it mediates non-homologous end-joining of chromosome ends and contributes to telomere-induced genomic instability.