An arresting tale

The external differences between species belie the fact that many of their genes, proteins and intracellular signalling pathways are very similar. So, for example, we can learn much about ourselves from studying such experimentally useful animals as the nematode Caenorhabditis elegans. Elsewhere in this issue (Nature 404, 782–787; 2000), however, René H. Medema and colleagues turn the tables. They describe a new branch of a signalling pathway in mammalian cells that may also offer insight into an important developmental state in C. elegans.

The story starts with humanity's fascination with extending life. For this reason, long-lived mutants of organisms such as C. elegans have received a lot of attention. By identifying the genes mutated in such organisms, we can get some idea about the proteins and signalling pathways involved in longevity. One pathway involves a cascade of enzymes known as kinases, culminating in the regulation of DAF-16 — a transcription factor of the so-called Forkhead family (see diagram). This pathway also regulates the developmentally arrested nematode larval state known as ‘dauer’, which occurs as a result of crowding and starvation.

Figure 1: Pathways involved in regulation DAF-16

At the cellular level, it is possible that, for a cell to stay alive, its death (by ‘apoptosis’) must be actively suppressed. In mammals, a pathway that represses apoptosis contains counterparts of many proteins from the nematode longevity pathway (see diagram; proteins that are conserved in the two pathways are shown in the same colours). This ‘survival’ pathway also ends with inhibition of members of the Forkhead family, resulting in repression of genes of the death machine.

Medema et al. now show that this signalling pathway has another, possibly more important, function: it puts a brake on the cell-division cycle. The authors find that signalling progresses along the now familiar enzymatic cascade, up to the point at which Forkhead proteins are regulated. Then, the pathway forks. One line leads to suppression of cell death, while the other leads to cell-cycle arrest — the key molecular effect here being an increase in levels of the protein p27^kip1. This appears to occur through increased expression of the gene encoding p27^kip1, rather than through stabilization of the p27^kip1 protein.

p27^kip1 is a well known molecule: it inhibits the activity of important regulators of the cell cycle, called cyclin/cyclin-dependent kinase (CDK) complexes. Increased p27^kip1 levels would be expected to lead to cell-cycle arrest in the period before DNA replication occurs. Such a block is exactly what Medema et al. find when they activate Forkhead proteins in mammalian cells.

This new prong of a known signalling pathway may provide an explanation for the proposed role of defects in this pathway in cancer — a condition that is essentially characterized by the undermining of the finely tuned molecular network that ensures controlled cell division and finite cellular lifespan. This story may also have come full circle in explaining why, in nematodes, this pathway blocks larval development.