Volume 11 Issue 11, November 2009

On the eve of budget decisions, the scale of cuts to basic research funding remains ill-defined.

Identifying therapies to slow down ageing and delay age-associated diseases is a primary goal of ageing-related research. Resveratrol and rapamycin were first found to promote longevity in yeast, and their effects were then extended to several organisms. Spermidine is a new longevity drug that can increase life span in yeast, nematodes and flies, possibly through an effect on chromatin-mediated regulation of gene expression.

The tumour suppressor Tip60 is a histone acetyltransferase implicated in transcriptional control and DNA double-strand break repair. Tip60 binds to the heterochromatic histone mark H3K9me3, triggering acetylation and activation of DNA double-strand break repair factors.

Intravital imaging demonstrates that TGF-β signalling regulates the mode of cancer cell motility. Cells with active TGF-β signalling migrate as single cells and are capable of hematogenous and lymphatic spread, whereas cells lacking TGF-β signalling invade lymphatics collectively.

In vivo imaging of mammary carcinoma cells reveals that activation of a TGFβ-induced transcriptional response induces the motility of individual cells, allowing them to spread through the blood stream. In the absence of TGFβ, cells migrate as groups and can only metastasize through the lymphatic system.

A screen for suppressors of breast to lung metastasis leads to the identification of KLF17 (Krüppel-like transcription factor 17), which is shown to be downregulated in breast cancer biopsies. KLF17 inhibits epithelial–mesenchymal transition and invasion by inhibiting the transcription of the metastasis factor Id1.

Administration of spermidine, a polyamine whose concentration declines during ageing, extends lifespan in yeast, flies, worms and in human immune cells. Spermidine prevents early oxidative stress and necrotic cell death and increases the expression of autophagy genes by inhibiting histone acetyltransferases action on histone H3.

Topoisomerase I, together with the splicing factor ASF/SF2, prevents the collapse of replication forks by inhibiting the formation of RNA–DNA hybrids during the transcription of genes localized at replicating forks, and thereby suppresses the genomic instability associated with such hybrids.

The Slit2 receptor Robo4 is known to maintain vascular permeability. Robo 4 prevents the formation of endothelial cell protrusions through a complex with paxillin and Arf–GAPs, which inhibits the GTPase Arf6a and thus leads to Rac activation.

IFT20, known to control intraflagellar transport during cilia biogenesis, is also expressed in lymphoid and myeloid non-ciliated cells. IFT20 is localized to the secretory pathway in T-lymphocytes and translocates to the immune synapse on antigen engagement to modulate the recycling of T-cell receptors.

The γ-secretase complex is responsible for the generation of amyloid β-peptide, the main component of Alzheimer's disease associated plaques. A proteomic analysis yielded secretory pathway components and membrane-associated tetraspannin microdomains as interactors and regulators of the γ-secretase complex.

Substrates of plant metacaspases, cystein proteases involved in plant programmed cell death (PCD), have been so far unknown. Metacaspase II is now shown to cleave the splicing regulator Tudor staphylococcal nuclease (TSN) during developmental and stress-induced PCD, an activity shared with caspase-3 during apoptosis in animals.

Two inhibitors of death receptor-associated apoptosis, cellular c-FLIP and viral v-FLIP prevents LC3 processing by Atg3 and thus repress the autophagic cell death that follows mTOR inhibition. Short peptides derived from FLIP can prevent Atg3–FLIP interaction without affecting Atg3–LC3, restoring cell death.

The anaphase-promoting complex (APC/C), a ubiquitin ligase regulating mitotic progression, is a target for spindle assembly checkpoint. UBE2S, an ubiquitin-conjugating enzyme, is identified as a novel factor that elongates ubiquitin chains and promotes APC/C substrate degradation following release from the spindle assembly checkpoint.

Parkin, an ubiquitin ligase whose mutations are associated with early development of Parkinson's disease, possesses a RING domain, suggesting it can modulate transcription. Parkin represses the expression of p53 both in fibroblasts and mice brains, independently of its ligase activity, and patient brain samples exhibit high levels of p53.

Tip60 acetylation of ATM kinase is necessary for DNA double-strand break repair and cancer suppression. Tip60 is recruited to breaks by histoneH3 trimethylated on lysine 9 and the Mre11/Rad50/Nbs1 damage response complex, activating its acetyltransferase activity.

The enzyme telomerase extends telomeres at unprotected chromosomal ends. DNA double-stranded breaks could also form a substrate for telomerase, but DNA damage signalling induces the phosphorylation of the telomerase inhibitor Pif1 at breaks, preventing ectopic addition of telomeres at sites of repair and hence genomic instability.