Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E

Abstract

Although mutations that activate the Hedgehog (Hh) signalling pathway have been linked to several types of cancer, the molecular and cellular basis of Hh's ability to induce tumour formation is not well understood. We identified a mutation in patched (ptc), an inhibitor of Hh signalling, in a genetic screen for regulators of the Retinoblastoma (Rb) pathway in Drosophila. Here we show that Hh signalling promotes transcription of Cyclin E and Cyclin D, two inhibitors of Rb, and principal regulators of the cell cycle during development in Drosophila. Upregulation of Cyclin E expression, accomplished through binding of Cubitus interruptus (Ci) to the Cyclin E promoter, mediates the ability of Hh to induce DNA replication. Upregulation of Cyclin D expression by Hh mediates the distinct ability of Hh to promote cellular growth. The discovery of a direct connection between Hh signalling and principal cell-cycle regulators provides insight into the mechanism by which deregulated Hh signalling promotes tumour formation.

Indian hedgehog: Its roles and regulation in endochondral bone development

“…Cyclin D1 promotes cell-cycle progression through G 1 /S phase transition and since cyclin D1 is expressed at low levels in slowly dividing reserve chondrocytes, but at high levels in rapidly dividing columnar chondrocytes [Yang et al, 2003] it was suggested that cyclin D1 mediates Ihh-dependent proliferative effects. This is supported by studies in Drosophila where Hh signaling directly induces cyclin D transcription through Ci [Duman-Scheel et al, 2002]. Similarly, Shh induces cyclin D expression in order to sustain cell cycle progression in mammalian neuronal precursor cells [Kenney and Rowitch, 2000].…”

The Drosophila wing differentiation factor Vestigial–Scalloped is required for cell proliferation and cell survival at the dorso-ventral boundary of the wing imaginal disc

“…44 Recently, the transcription factor Cubitus interruptus (Ci) was shown to mediate the effects of Hedgehog (Hh) signalling on cell growth and proliferation in the wing disc by direct binding to the Cyclin E promoter. 45 In addition, the Caudal (CAD) homeodomain protein was shown to bind the dE2F promoter in vitro, and CAD binding sites in the dE2F promoter are required for expression of dE2F in living flies. 46 These results most clearly demonstrate that developmental genes like Cad, Hh and Hox can directly regulate cell growth and proliferation.…”

Indian hedgehog gene transfer augments hematopoietic support of human stromal cells including NOD/SCID–ß2m–/– repopulating cells.

“…39 Furthermore, the molecular basis by which hedgehog accelerates the cell cycle, via the induction of cyclin D and cyclin E, has been reported recently. 40 Nevertheless, Ihh stromal cells, in which Ihh should work in a paracrine and/or autocrine fashion, did not exhibit growth acceleration. Moreover, they did not lose contact inhibition either in serum-free conditions or in LTC medium.…”