Retinoblastoma protein

• OMIM: 180200
• UniProt: P06400
• MGI: 97874

The retinoblastoma protein ( pRb, Rb ) is a tumor suppressor protein, which has an impaired function in many tumors. A very well-studied function of pRB is to slow down cell growth by the passage of the cell cycle is slowed down is. pRB is part of the so-called pocket protein family. Its members have a molecular pocket for binding to other proteins. If oncogene products as they are produced as in cells infected by human papilloma viruses bind to pRB, then this may lead to cancer.

Name and Genetics

Human pRb is encoded by a gene in the region of chromosome 13 q14.1 - q14.2. If both alleles of the gene are mutated, the affected patients develop retinoblastoma, hence the name. It is unknown as yet, why be developed with mutations of a gene that regulates the cell cycle in the whole human organism is a tumor of the eye. There are two forms of retinoblastoma: a familial bilateral and unilateral sporadic variant. In the former case the risk is to develop more tumors six times larger than the average. This fact illustrates the concept of Knudsonhypothese. This states that an allele of a tumor suppressor gene is sufficient for maintaining the function ( the mutated gene is recessive ) and therefore both must be mutated so that the tumor phenotype is visible. In the familial form of retinoblastoma, a mutant allele is inherited with a healthy allele. Then, when a further RB mutation occurs in a cell, all RB proteins in the cell are non-functional in terms of their ability to control the cell cycle. Thus, the cells can divide in an uncontrolled manner. This is an important step in carcinogenesis. As a result, increases the risk that tumors develop in all body cells, linearly .. It thereby also no need for direct mutation of the RB gene, a loss of heterozygosity (LOH ), which is frequently found in tumor cells, is sufficient.

In patients with the sporadic form of retinoblastoma, a new mutation of both alleles is necessary. This explains why the parties have no increased risk of developing other cancers, as two functional RB alleles are present in their body cells. The tumor incidence in patients with a sporadic form of retinoblastoma does not follow a quadratic kinetics. This would be expected, if the mutation of the two alleles is performed independently. In fact, follows the risk of further tumors of developing a polynomalen kinetics, indicating that can be triggered with a mutated RB gene, the mutation of the second allele by LOH a process in the cell in question and, therefore, happens more frequently than if this mutation would be independent of the first event.

Cell cycle regulation

PRB protects the cell against replicating damaged DNA by the cell is prevented from passing through the cell cycle through the G1 phase to the S phase. Binds Rb protein and inhibits the activity of transcription factors of the E2F family, composed of heterodimers of E2F protein and the DP protein.

The transcription activating complex of the "E2 promoter -binding protein - dimerization partners " ( E2F -DP) can push a cell into the S phase. As long as E2F -DP is inactivated, the cell will remain in the G1 phase. When pRB binds to E2F complex acts as a growth suppressor and hinder the progression through the cell cycle. The pRb-E2F/DP complex also binds a histone deacetylase (HDAC ) protein to chromatin and suppressed as additional DNA synthesis.

Activation and inactivation of pRb

The RB protein is activated by dephosphorylation and thus exerts its function as a tumor suppressor by regulatory influences the cell cycle. Phosphorylation inactivates the Rb protein. During the transition from the G1 phase to the M- pRB is increasingly dephosphorylated by PP1, and thus returns to its growth-inhibiting hypophosphorylated state.

If the cell cycle, the S phase begins pRB is phosphorylated by protein complexes of cyclin-dependent kinases ( CDK) and cyclins. pRB is inactivated in this way. Phosphorylation of pRB is started by the cyclin D/CDK4, 6, and continued by the cyclin E/CDK2. pRB is phosphorylated while the S, G2 and M phases. The phosphorylation of pRB allows the dissociation of the E2F -DP complex of pRB and activate this. In the unbound state, E2F activates the cyclins E and A, which drive the cell through the cell cycle by activating cyclin-dependent kinase and proliferating cell nuclear antigen PCNA. This accelerates DNA replication and DNA repair by DNA polymerases to bind to the DNA.