Research articles

The function of oxidation of specific proteins during apoptosis has been unclear. Oxidation of the actin-binding protein cofilin induces its translocation to the mitochondria, where it triggers the opening of the permeability transition pore independently of the BH3-only apoptotic factor Bax, and is required for oxidant-induced apoptosis.

p53-mediated replicative cellular senescence is a barrier to tumorigenesis. The p53 isoforms p53β and Δ133p53 are respectively induced and downregulated during replicative senescence. Elevated p53β and reduced Δ133p53 levels are observed in colon adenomas with senescent phenotypes, whereas the opposite is found in colon carcinomas that might have escaped from the senescence barrier.

The tumour suppressor p53 induces either apoptosis or cell-cycle arrest upon genotoxic stress. A regulatory network based on a complex of p53, the signalling protein axin, the p53 kinase HIPK2, the DNA repair-associated acetyltransferase Tip60 and Pirh2 governs the cellular response to p53 activation.

The RNA-binding protein Zcchc11 regulates cytokine expression in response to inflammation, although it was unclear how. Zcchc11 is shown to be an uridyltransferase that acts on mature cytokine-targeting miR-26b to influence interleukin-6 expression.

Meiosis I differs from meiosis II and mitosis in that sister kinetochores need to be co-oriented to segregate to the same pole. Mis12, a conserved component of the kinetochore core, is required to link kinetochores together during reductional division.

Dam1 is a component of the microtubule-binding DASH complex. Artificial recruitment of Dam1 to yeast mini-chromosomes can compete with endogenous kinetochores for microtubule binding and rescue chromosome segregation in the absence of centromeres.

Ask1 is a component of the microtubule-binding DASH kinetochore complex. Targeting Ask1 to a yeast plasmid lacking centromeres promotes the recruitment of other kinetochore components and rescues bi-orientation and chromosome segregation.

The ESCRT complex mediates sorting of ubiquitylated endosome-associated proteins into multivesicular bodies (MVBs). The RNA-induced silencing complex (RISC) components GW182 and AGO2 localize to membrane structures that congregate with MVBs. Loss of ESCRT function compromises miRNA-mediated silencing and increases GW182 levels, suggesting that ESCRT regulates RNAi by acting on GW182 turnover.

The Hermansky-Pudlak Syndrome 4 protein (HPS4) mediates trafficking between late endosomes and lysosomes and is now shown to inhibit small RNA-mediated silencing (RNAi) in flies and human cells. Components of the ESCRT complex, which mediates late endosome trafficking, are required for efficient miRNA-mediated silencing and additional results support the idea that RNAi effectors are functionally linked to endosome-associated compartments.

Ubiquitin-mediated degradation influences embryonic axis formation by regulating the stability of ventrally expressed transcription factors, although it is unclear whether dorsal factors are similarly modulated. In Zebrafish, the E3 ubiquitin ligase Lnx-l acts on the dorsal transcriptional repressor Boz to control dorso-ventral axis formation.

MicroRNAs are frequently expressed in clusters, which often prevent the attribution of an individual microRNA to a specific function. Single overexpression of miR17, a microRNA belonging to a six-microRNA cluster, shows it controls heart, spleen and liver development by targeting fibronectin.

Notch1 inhibits cardiac progenitor cell expansion by preventing the accumulation of phosphorylated β-catenin, which normally promotes their proliferation. In a feedback loop, Notch1 positively regulates the expression of cardiac transcription factors to induce progenitor cell differentiation, whereas β-catenin has the reverse effect.

The tumour suppressor protein VHL, which is inactivated in hereditary and sporadic forms of renal cell carcinoma, is found at the mitotic spindle in mammalian cells. VHL inactivation leads to unstable astral microtubules and spindle misorientation as well as to reduced levels of Mad2, resulting in spindle checkpoint weakening and genomic instability.

During neuronal development, the axonal growth rate is regulated in conjunction with pathfinding. Stimulation of localized mRNA translation of the polarity protein PAR3 by neural growth factor (NGF) and netrin-1 is now shown to be required for axonal outgrowth.

Pin1 regulates protein degradation and is now shown to control the ubiquitylation status of its targets. In yeast, Pin1 decreases the ubiquitylation of the transcription factor Spt23 to activate it, while low Pin1 levels increase its degradation. Similarly, inhibition of Pin1 in mammalian cells increases p53 ubiquitylation and nuclear degradation.

TGF-β mediates epithelial-mesenchymal transitions (EMT) during tumorigenesis but the molecular mechanisms driving this effect have been unclear. The transcriptional repressor SNAIL1 and the downstream effector of TGF-β SMAD3/4 cooperate to repress gene expression during TGF-β-mediated EMT.

Cells with a single short telomere and lacking telomerase continue to divide until they activate a Mec1/ATR-dependent checkpoint, causing senescence.

Persistent DNA damage activation and oncogene-induced senescence stimulate secretion of the inflammatory cytokine IL-6, which is mediated by the damage-response pathway including ATM, NBS1 and CHK2. Tumours with an activated DNA damage response show elevated IL-6 and invasiveness.

The Cdk4–pRb–E2F1 pathway is shown to have a role in insulin secretion in b cells by controlling the expression of a subunit of the K+ATP channel through E2F1 binding to its promoter.

Cells with a single short telomere and lacking telomerase mount a damage response consisting of recruitment of DNA damage checkpoint proteins, Cdc13, RPA and Rad52, many generations before senescence and in addition show tethering of the short telomere to the nuclear pore complex.