Reviews & Analysis

Hearing loss in mammals occurs when auditory hair cells, specialized in the detection of sound waves, undergo irreversible damage. However, the mechanism, and in particular the genetic basis of the process, is poorly understood. A study in this issue now shows that functional inactivation of the cyclin D-dependent kinase inhibitor Ink4d results in progressive hearing loss in mice, implicating Cdk inhibitors and inappropriate hair cell proliferation in deafness.

The ubiquitin-dependent N-end rule pathway targets proteins for degradation through their destabilizing N-terminal residues. This pathway is known to control the import of peptides, chromosome stability and cardiovascular development. A new report identifies yet another function of the N-end rule pathway: the regulation of apoptosis through degradation of Drosophila melanogaster DIAP1.

Sprouty proteins are antagonists of receptor tyrosine kinase (RTK) signalling in a number of developmental and physiological processes. A collection of work indicates that Sprouty proteins negatively and positively modulate RTK-induced signalling pathways through various mechanisms, thereby combining a variety of cellular functions in one molecule.

Cajal described the neural synapse as a “protoplasmic kiss”, and this metaphor applies equally well to the immunological synapse. Viruses are masters at co-opting the machinery of the immune response and, remarkably, the retrovirus HTLV-1 (human T lymphotrophic virus 1) seems to use an immunological-synapse-like structure to conceal viral spread.

The coordinated action of several conserved multiprotein complexes establishes polarity in an asymmetrically dividing cell. How apically localized cues affect the basal distribution of proteins has remained unclear. However, new studies provides a direct link between the two poles, showing that the apical Par6–aPKC complex directly regulates Lethal giant larvae (Lgl).

Cell polarity is regulated by independent pathways that are controlled by Wnt- or Cdc42-mediated signalling. Now, glycogen synthase kinase 3 (GSK-3), an established component of the Wnt pathway, is shown to interact with Par6–protein kinase C ζ (PKCζ), a complex that transduces Cdc42 signals. This exciting result suggests a potential point of conversion between these previously distinct pathways.

Apoptosis is a carefully orchestrated series of events that allows cells to be eliminated without damaging their neighbours. Regulation is essential, as too much apoptosis can contribute to neurodegenerative disorders, whereas too little can result in cancer. Two reports in this issue now demonstrate that Ku70, a protein previously shown to function in DNA repair, has an important role in regulating apoptotic events.

To coordinate the coding complexity of the eukaryotic genome, mechanisms have evolved that protect active genes from silent chromatin structures such as heterochromatin. Although post-translational modifications of histone tails can regulate chromatin states, a new report now demonstrates that the composition of the nucleosome itself is also important for maintaining chromatin states.

The multi-functionality of the adenomatous polyposis coli (APC) tumour suppressor gene keeps surprising cancer molecular biologists. Signal transduction, cytoskeletal organization, chromosomal segregation and cell adhesion are just some of the putative cellular functions previously assigned to this gene and thought to be related to its tumour-suppressing activity. New data on yet another tumour-related function of APC, namely the coordinated regulation of cell adhesion and motility, adds to its host of cellular activities.

Separase is a conserved protease that activates the metaphase-to-anaphase transition by cleaving the link between sister chromatids. Furthermore, in Saccharomyces cerevisiae, separase is also involved in promoting mitotic exit through regulating Cdc14 release. A new study now suggests that the mitotic exit function of separase is independent from its protease activity.

One of the earliest structural changes in cloning by nuclear transfer is the disassembly of the nucleolus. The first insights into the molecular mechanisms of this event have now emerged and the results have tantalising implications for nucleolar architecture.

GTP-binding proteins of the Rho family regulate each other's activities by largely elusive mechanisms. Now, an unexpected signalling pathway has been identified in fibroblasts that links Rac activation to the inhibition of Rho activity, through the release of oxygen radicals.