The Hedgehog-BMI1 Pathway
The Hedgehog-BMI1 Pathway
The Hedgehog (Hh) pathway regulates adult stem cell quiescence and self-renewal. Three Hh ligands
have been identified in mammals, Sonic hedgehog (Shh), Desert hedgehog (Dhh), and Indian hedgehog
(Ihh), of which Shh is the best studied. In the absence of ligand, the Hh receptor PTCH1 inhibits signaling
through the catalytic inhibition of the transmembrane protein Smoothened (SMO). Ligand occupation of
PTCH1 inactivates the receptor and allows activation of SMO that, in turn, results in the induction of Gli
transcription factors; Gli1 and Gli2 are positive mediators of Hh signaling while Gli3 is a negative
regulator.1,2
Many of the effects of Hh activation are facilitated by the induction of Bmi1, a polycomb gene that
represses transcription through chromatin remodeling and down-regulates the expression of genes in the
Ink-4A/ADP ribosylation factor (ARF) complex, such as p16 Ink4A and p19 ARF, that are negative
regulators of the cell cycle and are involved in stem cell quiescence and differentiation.1,3 This enables
stem cell proliferation and self-renewal via the Gli1- and Gli2-induced expression of the growth promoting
genes cyclin D1, Myc, and Snail as well as upregulation of the Hh pathway elements PTCH1, Gli1, and
Gli2.2,4
References
1. Liu, S., et al., Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant
human mammary stem cells. Cancer Res., 66, 6063-6071 (2006).
2. Peacock, C.D., et al., Hedgehog signaling maintains a tumor stem cell compartment in multiple
myeloma. Proc. Natl. Acad. Sci. USA, 104, 4048-4053 (2007).
3. Massard, C., et al., Tumor stem cell-targeted treatment: elimination or differentiation. Ann. Oncol.,
17, 1620-1624 (2006).
4. Mimeault, M., and Batra, S.K., Interplay of distinct growth factors during epithelial-mesenchymal
transition of cancer progenitor cells and molecular targeting as novel cancer therapies. Ann. Oncol.,
18, 1605-1619 (2007).