Tumour suppressor genes

Tumor suppressor genes can induce malignant transformation of a cell alongside proto-oncogenes and mutator genes.

The products of tumor suppressor genes primarily regulate the cell cycle, and some also participate in DNA repair processes.

In contrast to the products of proto-oncogenes, the products of tumor suppressor genes mainly have antiproliferative effects, supporting differentiation and apoptosis.

Disruption of cell cycle control can result from:

1. loss of both alleles of a particular tumor suppressor gene (e.g., due to deletion)
2. structural changes (e.g., point mutation)
3. inactivation of the protein product encoded by the gene

Mutations in tumor suppressor genes are recessive in nature.

This relates to the so-called two-hit hypothesis, which was first explained in relation to the development of the rare hereditary retinoblastoma. Unlike the much more common sporadic retinoblastoma, where random mutations affect one allele and subsequently the second in retinal cells, the hereditary form involves inheriting one mutated allele. The individual is thus a heterozygote with a latent predisposition to tumor development.

If a mutation or loss affects the second allele, a clone of tumor cells in the retina can begin to develop.

This process is known as loss of heterozygosity (LOH).

Examples

Among the most significant tumor suppressor genes are Rb, p53, BCR1, BCR2, and others.

Rb gene

The Rb gene (Retinoblastoma) was the first discovered tumor suppressor gene. It is present in every cell, where it regulates the cell cycle. Its product, the Rb protein, along with p53 protein, acts as a kind of brake on cell proliferation.

Rb negatively regulates an important transcription factor called E2F. Deletion of the Rb gene, which occurs during congenital retinoblastoma, or sequestration of its product by adenoviral protein E1A or protein E7 (from human papillomavirus infection) results in the release of E2F suppression.

Virogenic products such as E1A (from adenovirus) or E7 (from human papillomavirus) bind to Rb and have similar effects.Loss of Rb's regulatory function in the cell cycle or overexpression of c-myc leads to increased proliferation—but also to increased apoptosis of the affected cells.

At this stage, the number of transformed cells does not yet increase significantly. However, a subsequent change—such as loss of p19ARF, mutation of p53, or overexpression of bcl-2 leads to increased proliferation and decreased apoptosis.

p53

P53 pathways

In contrast, p53 acts by promoting the expression of p21/CIP, a powerful inhibitor of cyclin-dependent kinases, which regulate the cell cycle.

The p53 gene also plays a role in the second checkpoint of interphase—by pausing the cell cycle during this period, it enables post-replication repair. If repair fails, p53 initiates and coordinates apoptosis.

The interaction of p53 is often one of the earliest steps leading to malignant transformation in the development of many cancers.

Patients with Li-Fraumeni syndrome usually carry one mutated allele in their germline cells, which significantly increases their risk of developing sarcomas, leukemia, and breast cancer.

The p53 gene is also referred to as the guardian of the genome, as it responds to DNA damage by temporarily halting the cell cycle, thereby allowing for error repair (the so-called "major repair").

Sources

MATOUŠ, Bohuslav, et al. Základy lékařské chemie a biochemie. 1. vydání. Praha : Galén, 2010. 540 s.