Tumour Suppressor Genes

Abstract

Tumour suppressor genes are a group of genes whose loss contributes to malignancy. The original hypothesis surrounding tumour suppressor genes defined a ‘two‐hit’ requirement for mutagenesis; however, it is now known that deletion, silencing or downregulation of one or more genes may lead to cancer formation. There is a growing list of putative tumour suppressor genes, and recently several new candidates were added. Research into apoptosis, or programmed cell death, continues to expand. As pathways for which tumour suppressor genes are responsible become clearer, so do potential therapeutics to capitalise on these targets. A summary of the mechanisms by which tumour suppressor genes may act, the mutations which lead to tumourigenesis, and the clinical implications of these phenomena are presented.

Key Concepts:

  • Tumour suppressor genes prevent mutagenesis.

  • Perturbation of tumour suppressor gene function may lead to cancer formation.

  • The first tumour suppressor gene identified was the Rb gene, and mutations in the gene lead to the childhood cancer known as retinoblastoma.

  • Although many tumour suppressor genes require two mutations to cause a loss‐of‐function, in some cases, downregulation of a single tumour suppressor gene may lead to cancer.

  • The p53 gene is involved in a complex pathway of cell death and cell arrest, and mutations in p53 or other genes in the pathway can lead to the development of cancer.

  • There are several other modulators of tumour formation, including telomeres, adhesion molecules and microRNA, that may function like tumour suppressor genes.

  • Identification of tumour suppressor genes has lead to the development of anticancer therapeutic agents targeted to specific pathways that take advantage of this knowledge.

Keywords: oncogene; cancer; tumour; tumour suppressor; p53; apoptosis

Figure 1.

The p53 tumour suppressor resides at a pivotal point in responding to stress and cellular growth state. A variety of kinases modulate p53 in response to stresses such as deoxyribonucleic acid (DNA) damage, thereby inhibiting the normally rapid degradation of p53. Alternatively, the alternative reading frame (ARF) gene product (encoded at the Ink4a tumour suppressor locus) represses Mdm‐2 from its inhibition and its targeting of p53 for destruction. ARF may be upregulated by the S‐phase transcription factor E2F. Once upregulated by these events, p53 can trigger either cell cycle arrest or apoptosis (the latter pathway being subject to regulation by the Bcl‐2–Bax family of proteins), dependent on a complex system of yet uncharacterised events leading to co‐repression and activation of transcriptional elements.

Figure 2.

Cell cycle modification by the tumour suppressors p53, p27 and p16. p53 responds to DNA damage, in addition to other signal pathways, inducing either cell cycle arrest, as mediated by p21 and Rb inhibition of E2F, or apoptosis, via a Bax‐mediated pathway.

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How to Cite close
Skolnik, Jeffrey M, and Fisher, David(Feb 2011) Tumour Suppressor Genes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001475.pub2]