Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E.
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.
Duman-Scheel
Molly
M
Ben May Institute for Cancer Research and Center for Molecular Oncology, The University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637, USA.
Weng
Li
L
Xin
Shijie
S
Du
Wei
W
D000818:Animals; D001973:Bromodeoxyuridine; D002455:Cell Division; D056741:Cyclin D; D019927:Cyclin E / Q000235:genetics*; D016213:Cyclins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D005123:Eye / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011956:Receptors, Cell Surface; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D014157:Transcription Factors
C534694:CycD protein, Drosophila; D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D019476:Insect Proteins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C092937:ci protein, Drosophila; C070844:ptc protein, Drosophila; C077245:hh protein, Drosophila; D001973:Bromodeoxyuridine