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The ID proteins: master regulators of cancer stem cells and tumour aggressiveness

Key Points

  • Inhibitor of DNA binding (ID) proteins are a family of highly conserved transcriptional regulators that are pivotal both during developmental processes and in adult tissue homeostasis. ID proteins function by inhibiting basic helix–loop–helix, ETS and paired box (PAX) transcription factors and non-transcription factors of the RB family.

  • The major biological effect of ID protein activity is the inhibition of differentiation and maintenance of self-renewal and multipotency in stem cells, and this is coordinated with continuous cell cycling.

  • ID proteins are essential components of oncogenic pathways and are activated transcriptionally and post-transcriptionally by oncogenic factors. ID proteins are repressed by tumour suppressors although they have also been shown to function as tumour suppressors in specific tumour types.

  • ID proteins are overexpressed in many human cancers and deregulation of ID proteins has a direct role in cancer initiation, maintenance, progression and drug resistance.

  • The expression of ID proteins has a prognostic value in many human cancers and interfering with ID activity in tumours that have ID protein activation might provide new avenues for cancer treatment.

Abstract

Inhibitor of DNA binding (ID) proteins are transcriptional regulators that control the timing of cell fate determination and differentiation in stem and progenitor cells during normal development and adult life. ID genes are frequently deregulated in many types of human neoplasms, and they endow cancer cells with biological features that are hijacked from normal stem cells. The ability of ID proteins to function as central 'hubs' for the coordination of multiple cancer hallmarks has established these transcriptional regulators as therapeutic targets and biomarkers in specific types of human tumours.

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Figure 1: ID proteins: proliferation and inhibition of differentiation.
Figure 2: Regulation of ID protein expression by oncogenes and tumour-suppressor genes.
Figure 3: Control of ID protein stability by ubiquitin ligases and deubiquitylating enzymes.
Figure 4: ID proteins and the perivascular niche.

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Acknowledgements

The authors thank L. Barret and A. Castano for critical reading of the manuscript. This work was supported by US National Institutes of Health (NIH) grants to A.L., R.B. and A.I.

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Correspondence to Antonio Iavarone.

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Glossary

Cancer stem cells

A small population of cells that is found in most types of cancer; these cells have the ability to drive tumour growth and spread through self-renewing cell divisions.

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Transcription factors that can work in a dimeric state and bind to specific DNA sequences via the stretch of basic amino acids.

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(EMT). A functional transition in which epithelial cells lose their cell polarity and cell–cell adhesion and assume a mesenchymal cell phenotype, which includes migratory and invasive properties.

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(TNBC). A highly aggressive subtype of breast cancer that is defined by the absence of oestrogen receptor, progesterone receptor and ERBB2 gene amplification.

Burkitt's lymphoma

An aggressive neoplasm that is derived from mature B cells and is cytogenetically characterized by the t(8;14) translocation that deregulates MYC.

Transit-amplifying progenitors

The progeny of stem cells that differentiate after a definite number of cell divisions.

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A device that uses the principles of osmotic pressure for the controlled delivery of drugs.

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Lasorella, A., Benezra, R. & Iavarone, A. The ID proteins: master regulators of cancer stem cells and tumour aggressiveness. Nat Rev Cancer 14, 77–91 (2014). https://doi.org/10.1038/nrc3638

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