Mutations that activate the Hedgehog (Hh) signalling pathway have been linked to tumour formation, but it's not been clear how. The discovery of a direct link between Hh signalling and key regulators of the cell cycle might now provide the answer.

Wei Du and colleagues were studying eye development in Drosophila melanogaster. The expression pattern of Hh during this process, just posterior to cells entering S phase, indicated that reception of the Hh signal might be needed for entry to S phase. To test this, the authors looked at what would happen if Hh signalling was blocked during eye development. They found that second mitotic wave cells with mutated smoothened (smo), a gene that is required for Hh signalling, do not enter S phase. By contrast, overexpression of Cubitus interruptus (Ci) — the transcription factor that mediates Hh signalling — drove G1-arrested cells to enter S phase.

One protein that promotes S phase is Cyclin D. During eye development, the highest expression of Cyclin D overlaps with that of Ci — so could Ci promote the expression of Cyclin D? Support for this idea came from the observation that levels of Cyclin D are reduced in smo-mutant clones, and also that overexpression of Ci induces high levels of Cyclin D messenger RNA and protein.

As well as promoting entry into S phase, Cyclin D induces cell growth. Du and co-workers therefore wondered whether Hh might also regulate growth, so they studied the effects of overexpressing either Ci or Patched (Ptc; an inhibitor of Hh signalling) in clones of undifferentiated wing-disc cells. Whereas Ptc overexpression clones were considerably smaller than controls, Ci overexpression clones were much larger, which indicates that Hh signalling not only promotes S phase, but that it also regulates cell growth.

Cyclin E also promotes S phase, and reduced or increased levels of this protein could be detected with loss of smo or overexpression of Ci, respectively. The authors then looked at how Hh signalling might induce the transcription of Cyclin E. They identified several sequences in the Cyclin E promoter with homology to the consensus Ci-binding site, and used chromatin immunoprecipitation to show that Ci indeed binds these sites in vivo. Hh signalling therefore seems to promote S phase by direct induction of Cyclin E expression, as well as Cyclin D.

This study shows a direct link between Hh signalling and cell growth (though Cyclin D) and proliferation (through both Cyclin D and Cyclin E). And, as the authors conclude, “constitutive Hh signalling, which promotes deregulated expression of G1–S cyclins that have been associated with diverse forms of human cancer, would promote both cell proliferation and growth in tumours”.