Volume 13 Issue 3, March 2011

The adult human heart lacks sufficient regenerative capacity to recover after a myocardial infarction. Cell-based therapy has emerged as a potential treatment for the failing heart; however, a key issue for the success of future cell-based therapies is the ability to obtain patient-specific high-quality cardiomyocytes in a fast and efficient manner. Recent progress has been made towards this goal using reprogramming-based approaches.

Cellular senescence is a potent tumour suppressor mechanism that is often accompanied by activation of DNA damage response (DDR) signalling and marked heterochromatinization. Senescence-associated heterochromatin is now shown to limit DDR, thus reducing apoptosis and promoting survival of senescent cells.

Glucose is an important source of energy and carbon, and is required for cell growth. As such, glucose utilization is increased in rapidly dividing cancer cells. The tumour suppressor p53 has now been reported to block a metabolic pathway (the pentose phosphate pathway) that diverts glucose away from bioenergetic into biosynthetic routes.

In response to major cellular insults, a massive increase in lysosomal membrane permeability (LMP) leads to necrosis. Data now reveal that this potent lysosomal-mediated necrotic cell-death machinery can also be harnessed for complex physiological processes, such as post-lactation mammary gland involution.

Aneuploidy is one of the most prevalent phenotypes of human tumours, but the underlying cause of this phenomenon remains highly debated. Entosis, the invasion of a living cell into another cell's cytoplasm, is now shown to perturb cytokinesis and induce the formation of aneuploid cells.

A conditional knockout of the transcription factor SRF in the mouse skin shows that SRF-mediated modulation of actin regulator transcription during development is essential for normal cortical network formation and correct spindle orientation in mitosis.

Reprogramming cells towards pluripotency by expression of Oct4, Sox2, Klf4 and c-Myc can be directed towards cardiogenesis by changing the cell culture medium, leading to the formation of spontaneously contracting patches of differentiated cardiomyocytes within ten days.

APC/C-Cdc20 ubiquitylates different substrates at distinct times during the cell cycle. This substrate specificity is now shown to depend on the differential binding of Cdc20 to APC subunits in response to the state of activation of the spindle assembly checkpoint.

Successful completion of the S phase in fission yeast is needed for the switch from monopolar to bipolar growth. The DNA replication checkpoint kinase Cds1 is found to regulate this process by modulating the activity of microtubule plus-end binding proteins that are responsible for cell growth.

53BP1 is marker of double-strand breaks and accumulates in nuclear foci. These foci are shown to accumulate in G1 at lesions generated by replication stress and may shield lesions from erosion.

The senescence-associated secretory phenotype (SASP) is a hallmark of senescent cells, but the mechanisms underlying cytokine secretion were unknown. Klotho, a protein with purported anti-ageing effects, is now shown to inhibit RIG-I-mediated secretion of IL-6 and IL-8 during replicative senescence.

Under conditions of energy starvation, the p38β–PRAK pathway is activated and inhibits mTORC1 by phosphorylating the small GTPase Rheb. This finding links a major stress response pathway with energy homeostasis.

The deubiquitylating enzyme ataxin 3 causes polyglutamine disease. In Caenorhabditis elegans, an ataxin-3 orthologue cooperates with the ubiquitin-selective chaperone CDC-48/p97 to control lifespan in a manner that may involve ubiquitin chain editing.

Oncogenic Ras is known to activate the Raf–MEK–ERK phosphorylation cascade to promote mitogenic signalling. Ras also inhibits the downregulation of MAPK pathway activity by preventing the MEKK1 SUMO E3 ligase from sumoylating and inactivating MEK.

Different mechanisms have been implicated in the induction of senescence. Two of these mechanisms, the DNA damage response, which induces a replicative checkpoint, and the formation of heterochromatic foci, which leads to transcriptional repression, are found to act together in oncogene-expressing cells.

Post-lactational involution in the mammary gland is shown to be accomplished by a lysosome-mediated cell death pathway. This pathway is independent of the executioner caspases 3, 6 and 7, and instead relies on Stat3-mediated upregulation of cathepsins.

Cancer cells preferentially use aerobic glycolysis to generate ATP, consuming glucose in the process. The tumour suppressor p53 is now shown to suppress glucose consumption by inhibiting the pentose phosphate pathway (PPP). Tumour-associated p53 mutations lack this inhibitory effect.

The epithelial to mesenchymal transition (EMT) has been recently associated with a stem cell phenotype. In breast cancer cell lines and tumours, p53 directly targets the expression of microRNAs that have been shown to inhibit EMT and stem cells regulators.

Aneploidy is frequently observed in cancer. It is now shown that aneploidy can arise by entosis, the process of live cell internalisation by a neighbouring cell. The internalised cell can interfere with host cell division and disrupt the formation of the contractile actin ring resulting in cytokinesis defects and aneuploidy.

Genome editing mediated by zinc finger nucleases can be used to generate fluorescently labelled proteins that are expressed at endogenous levels from their native genetic loci. Applying this technology to the clathrin light chain A and dynamin-2 loci reveals that clathrin-mediated endocytosis is more regular and efficient than previously thought.