Key Points
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Signalling between Notch receptors and ligands influences many differentiation processes and cell-fate decisions during embryonic and postnatal development.
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Stem-cell maintenance, binary cell-fate decisions and induction of differentiation are three main functions of Notch signalling in self-renewing tissues.
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Notch can function as an oncogene. Aberrant expression of the dominant active cytoplasmic domain of Notch receptors in haematopoietic cells because of chromosomal translocation or viral integrations causes T-cell leukaemias in mice and humans.
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Notch needs to cooperate with oncoproteins that can override the G1–S checkpoint in order to cause cancer.
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Notch receptors and ligands are re-expressed in certain human carcinomas, which is compatible with the ability of Notch to maintain stem cells or precursor cells in an undifferentiated state.
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Recent data show that Notch1 can also function as a tumour suppressor in mouse skin by inducing Waf1 and repressing Shh and Wnt signalling.
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Notch has two faces; one that promotes and the other that suppresses tumorigenesis. Which of the two faces is shown is dependent on the cellular context and the crosstalk with other signal-transduction pathways.
Abstract
Notch signalling participates in the development of multicellular organisms by maintaining the self-renewal potential of some tissues and inducing the differentiation of others. Involvement of Notch in cancer was first highlighted in human T-cell leukaemia, fuelling the notion that aberrant Notch signalling promotes tumorigenesis. However, there is mounting evidence that Notch signalling is not exclusively oncogenic. It can instead function as a tumour suppressor.
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Acknowledgements
We apologize to colleagues whose work was not referenced because of space limitations. Research in the Radtke lab is supported by grants from the Swiss Cancer League, the National Science Foundation, the Leenaards Foundation and the European Molecular Biology Organization Young Investigator Programme. Research in the Raj lab is supported by the National Centre of Competence in Research programme of the Swiss National Science Foundation. We thank J. Hornfeld and M. Migliaccio for careful reading of the manuscript and comments. We are also grateful to the anonymous referees, whose constructive suggestions helped improve this review.
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Glossary
- HAPLOINSUFFICIENCY
-
A situation in which a loss-of-function phenotype is produced by mutation of one allele of a gene in a diploid cell, even though the other allele is wild type.
- FUCOSE RESIDUES
-
Sugar residues that are attached to certain EGF repeats of Notch receptors. In the presence of the corresponding saccharides, Fringe proteins can elongate these sugar chains.
- BINARY CELL-FATE DECISION
-
The situation in which a precursor cell has to choose between two different cell fates.
- MYELOID ORIGIN
-
Cells of myeloid origin include macrophages, granulocytes, megakaryocytes, erythroblasts and myeloid-dentritic cells, whereas cells of lymphoid origin include T cells, B cells, natural-killer cells and lymphoid dendritic cells.
- ERBB2
-
A receptor tyrosine kinase that is overexpressed and activated in many tumours, especially in breast cancers.
- ANOIKIS
-
Cell death induced as a result of the absence of matrix attachment.
- SUPRABASAL LAYERS
-
The layers of the skin comprising the spinous and the granular layers.
- SENESCENCE
-
The irreversible loss of the proliferation potential, mainly caused by shortening and dysfunction of telomeres. However, it can also be caused by suboptimal culture condition, termed culture shock.
- p63
-
p63 is a homologue of the tumour suppressor p53 and the related protein p73. The TP63 gene encodes several isotypes with divergent abilities to transactivate p53 reporter genes and to induce apoptosis. The predominant p63 isotypes in many epithelial tissues lack the acidic amino terminus (so are known as ΔNp63), which corresponds to the transactivation domain of p53, and therefore lack transactivation function.
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Radtke, F., Raj, K. The role of Notch in tumorigenesis: oncogene or tumour suppressor?. Nat Rev Cancer 3, 756–767 (2003). https://doi.org/10.1038/nrc1186
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DOI: https://doi.org/10.1038/nrc1186
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