Tumor suppressor gene

 Tumor suppressor genes 

Tumor suppressor genes (also called anti-oncogenes or recessive oncogenes) have a fundamental role in the malignant process. Their products regulate cell division. The absence of both alleles of a certain suppressor gene (e.g. deletion), a change in their structure (e.g. point mutation) or the inactivation of the protein encoded by them leads to a cell cycle control disorder. All this can result in a malignant transformation of the cell.

 General 

The principle of the two-hit theory in retinoblastoma

Mutations in tumor suppressor genes are recessive in nature. Unlike oncogenes, the proteins encoded by anti-oncogenes have an anti-proliferative effect, promote differentiation and apoptosis.

There are about 40 tumor suppressor genes in each somatic cell. To become tumorigenic, both of their alleles must be mutated – hence the name recessive oncogenes. This is related to the so-called double-hit theory (first formulated by Knudson when explaining the occurrence of rare hereditary retinoblastoma). In contrast to the much more common sporadic retinoblastoma, where there are random mutations of one and then the other allele in the retinal cell, in the hereditary form one mutated allele is inherited. The relevant individual is a heterozygote in whom the inherited tumor predisposition has not yet manifested itself. However, if the second allele is mutated/eliminated, the development of a tumor clone of retinal cells is initiated.

This process is called loss of heterozygosity (LOH – loss of heterozygosity).

 pRB 

The CDK4/Cyclin D complex phosphorylates the pRB/E2F complex and thereby releases the E2F transcription factor, which further enables the cell to transition from G1 to S phase

The first discovered tumor suppressor gene was called the retinoblastoma gene (RB1 gene) and its product RB-protein (pRB). It occurs in every cell, where it regulates the cell division cycle.

Retinoblastoma gene (RB1) and another tumor suppressor gene TP53, respectively. their products act as a kind of brake on cell proliferation. RB1 negatively regulates the important transcription factor E2F. Deletion of the RB1 gene, which occurs in hereditary retinoblastoma, or sequestration of its protein product in the presence of adenoviral protein E1A or protein E7 (in human papillomavirus infection) induces unblocking of E2F suppression. In contrast, p53 acts by promoting the expression of p21/CIP, which is a potent inhibitor of cell cycle-regulating kinases (cyclin-dependent kinases).

Loss of the regulatory function of the Rb-gene in the cell cycle or overexpression of c-myc lead to increased proliferation, but also to increased apoptosis of the affected cells. Virogenic products such as E1A (adenovirus infection), T121-antigen (from SV-virus) or E7 (from human papillomavirus) bind to Rb and then have a similar effect. At this stage, the number of transformed cells does not increase yet. However, another genetic change, causing loss of p19ARF, mutation of p53, or overexpression of bcl-2, leads to increased proliferation and decreased apoptosis. Contributing to this are gene products such as E1b (from adenovirus), large antigen from SV-virus and E-6 antigen from papillomavirus, which bind to the p53 protein. Apoptosis, or the tendency to decrease it, is of key importance for the development of tumorigenesis.

 p53 

The tumor suppressor gene TP53, which encodes the p53 protein, is a key regulatory factor that monitors DNA damage. Inactivation of p53 is usually one of the first steps that leads to malignant transformation in the development of a number of cancer diseases. Patients with Li-Fraumeni syndrome usually have one mutant allele in their germ cells and thus an increased risk of developing sarcomas, leukemia and breast cancer.

Located on the short arm of chromosome 17 (17p13.1, OMIM: 191170), it contains 393 codons, regulates the progress of interphase, also called the "guardian of the genome". It reacts to DNA damage by temporarily suspending the cycle and thus enables error repair (the so-called big repair). CAVE!!! The p53 gene is not directly responsible for cycle arrest or error repair. It controls the initiation and duration of the resting stage through genes whose transcriptional activity is controlled by its p53 protein.

The p53 gene is also used in the 2nd interphase checkpoint - by pausing the cell cycle in this period, it enables the so-called post-replication repair. Furthermore, it induces and coordinates apoptosis when DNA repair is not successful.

Overview of some recessive oncogenes causing cancer Links

Source

ŠTEFÁNEK, Jiří. Medicine, diseases, studies at the 1st Faculty of Medicine, UK [online]. [feeling. 11/02/2010]. < https://www.stefajir.cz/ >.

MASOPUST, Jaroslav. Pathobiochemistry of the cell [online]. ©2003. [feeling. 17.03.2011]. < http://dotdiag.cz/img/prednasky/bunka.pdf >.