Retinoblastoma protein

"RB1" redirects here. For the automobile, see Red Bull RB1.

The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated RB or RB1) is a tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. When the cell is ready to divide, pRb is phosphorylated, becomes inactive and allows cell cycle progression. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.

Rb belongs to the pocket protein family, whose members have a pocket for the functional binding of other proteins. Should an oncogenic protein, such as those produced by cells infected by high-risk types of human papillomaviruses, bind and inactivate pRb, this can lead to cancer.

Name and genetics

In humans, the protein is encoded by the RB1 gene located on 13q14.1-q14.2. If both alleles of this gene are mutated early in life, the protein is inactivated and results in development of retinoblastoma cancer, hence the name Rb. Retinal cells are not sloughed off or replaced, and are subjected to high levels of mutagenic UV radiation, and thus most pRB knock-outs occur in retinal tissue (but it's also been documented in certain skin cancers in patients from New Zealand where the amount of UV radiation is significantly higher).

Two forms of retinoblastoma were noticed: a bilateral, familial form and a unilateral, sporadic form. Sufferers of the former were 6 times more likely to develop other types of cancer later in life. This highlighted the fact that mutated Rb could be inherited and lent support to the two-hit hypothesis. This states that only one working allele of a tumour suppressor gene is necessary for its function (the mutated gene is recessive), and so both need to be mutated before the cancer phenotype will appear. In the familial form, a mutated allele is inherited along with a normal allele. In this case, should a cell sustain only one mutation in the other RB gene, all Rb in that cell would be ineffective at inhibiting cell cycle progression, allowing cells to divide uncontrollably and eventually become cancerous. Furthermore, as one allele is already mutated in all other somatic cells, the future incidence of cancers in these individuals is observed with linear kinetics. The working allele need not undergo a mutation per se, as loss of heterozygosity (LOH) is frequently observed in such tumours.

However, in the sporadic form, both alleles would need to sustain a mutation before the cell can become cancerous. This explains why sufferers of sporadic retinoblastoma are not at increased risk of cancers later in life, as both alleles are functional in all their other cells. Future cancer incidence in sporadic Rb cases is observed with polynomial kinetics, not exactly quadratic as expected because the first mutation must arise through normal mechanisms, and then can be duplicated by LOH to result in a tumour progenitor.

RB1 orthologs have also been identified in most mammals for which complete genome data are available.

RB/E2F-family proteins repression transcription.

Cell cycle suppression

Rb restricts the cell's ability to replicate DNA by preventing its progression from the G1 (first gap phase) to S (synthesis phase) phase of the cell division cycle. Rb binds and inhibits transcription factors of the E2F family, which are composed of dimers of an E2F protein and a dimerization partner (DP) protein. The transcription activating complexes of E2 promoter-binding–protein-dimerization partners (E2F-DP) can push a cell into S phase. As long as E2F-DP is inactivated, the cell remains stalled in the G1 phase. When Rb is bound to E2F, the complex acts as a growth suppressor and prevents progression through the cell cycle. The Rb-E2F/DP complex also attracts a histone deacetylase (HDAC) protein to the chromatin, reducing transcription of S phase promoting factors, further suppressing DNA synthesis.

Detection

Several methods for detecting the RB1 gene mutations have been developed including a method that can detect large deletions that correlate with advanced stage retinoblastoma.

Activation and inactivation

See also: cyclin-dependent kinase and DREAM complex

Rb is phosphorylated to pRb by certain cyclin-dependent kinases (CDKs). pRb is described as being hyperphosphorylated and when in this state, it is unable to complex E2F and therefore, unable to restrict progression from the G1 phase to the S phase of the cell cycle. During the M-to-G1 transition, pRb is progressively dephosphorylated by PP1, returning to its growth-suppressive hypophosphorylated state Rb .

When it is time for a cell to enter S phase, complexes of cyclin-dependent kinases (CDK) and cyclins phosphorylate Rb to pRb, inhibiting its activity. The initial phosphorylation is performed by Cyclin D/CDK4/CDK6 and followed by additional phosphorylation by Cyclin E/CDK2. pRb remains phosphorylated throughout S, G2 and M phases.

Phosphorylation of Rb allows E2F-DP to dissociate from pRb and become active. When E2F is free it activates factors like cyclins (e.g. Cyclin E and A), which push the cell through the cell cycle by activating cyclin-dependent kinases, and a molecule called proliferating cell nuclear antigen, or PCNA, which speeds DNA replication and repair by helping to attach polymerase to DNA.

Rb family proteins are components of the DREAM complex (also named LINC complex), which is composed of LIN9, LIN54, LIN37, MYBL2, RBL1, RBL2, RBBP4, TFDP1, TFDP2, E2F4 and E2F5. There is a testis-specific version of the complex, where LIN54, MYBL2 and RBBP4 are replaced by MTL5, MYBL1 and RBBP7, respectively. In Drosophila both DREAM versions also exist, the components being mip130 (lin9 homolog, replaced by aly in testes), mip120 (lin54 homolog, replaced by tomb in testes), and Myb, Caf1p55, DP, Mip40, E2F2, Rbf and Rbf2. The DREAM complex exists in quiescent cells in association with MuvB (consisting of HDAC1 or HDAC2, LIN52 and L3mbtl1, L3mbtl3 or L3mbtl4) where it represses cell cycle-dependent genes. DREAM dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2.

Regeneration

Cochlea

The retinoblastoma protein is involved in the growth and development of mammalian hair cells of the cochlea, and appears to be related to the cells' inability to regenerate. Embryonic hair cells require Rb, among other important proteins, to exit the cell-cycle and stop dividing, which allows maturation of the auditory system. Once wild-type mammals have reached adulthood, their cochlear hair cells become incapable of proliferation. In studies where the gene for Rb is deleted in mice cochlea, hair cells continue to proliferate in early adulthood. Though this may seem to be a positive development, Rb-knockdown mice tend to develop severe hearing loss due to degeneration of the organ of Corti. For this reason, Rb seems to be instrumental for completing the development of mammalian hair cells and keeping them alive. However, it is clear that without Rb, hair cells have the ability to proliferate, which is why Rb is known as a tumor suppressor. Temporarily and precisely turning off Rb in adult mammals with damaged hair cells may lead to propagation and therefore successful regeneration. Suppressing function of the retinoblastoma protein in the adult rat cochlea has been found to cause proliferation of supporting cells and hair cells. Rb can be downregulated by activating the sonic hedgehog pathway, which phosphorylates the proteins and reduces gene transcription.

Neurons

Disrupting Rb expression in vitro, either by gene deletion or knockdown of Rb short interfering RNA, causes dendrites to branch out farther. In addition, Schwann cells, which provide essential support for the survival of neurons, travel with the neurites, extending farther than normal. The inhibition of Rb supports the continued growth of nerve cells.

Interactions

Retinoblastoma protein has been shown to interact with:

• Abl gene
• Androgen receptor
• Apoptosis-antagonizing transcription factor
• ARID4A
• Aryl hydrocarbon receptor
• BRCA1
• BRF1
• C-jun
• C-Raf
• CDK9
• CUTL1
• Cyclin A1
• Cyclin D1
• Cyclin T2
• DNMT1
• E2F1
• E2F2,
• E4F1
• EID1
• ENC1
• FRK
• HBP1
• HDAC1
• HDAC3
• Histone deacetylase 2
• Insulin
• JARID1A
• LIN9
• MCM7
• MORF4L1
• MRFAP1,
• MyoD
• NCOA6
• PA2G4
• Peroxisome proliferator-activated receptor gamma
• PIK3R3
• Plasminogen activator inhibitor-2
• Polymerase (DNA directed), alpha 1
• PRDM2
• PRKRA
• Prohibitin
• Promyelocytic leukemia protein
• RBBP4
• RBBP7
• RBBP8
• RBBP9
• SNAPC1
• SKP2
• SNAPC3
• SNW1
• SUV39H1
• TAF1
• THOC1
• TRAP1
• TRIP11
• UBTF
• USP4.

Overview of signal transduction pathways involved in apoptosis.

See also

• p53 - involved in the DNA repair support function of pRb
• Transcription coregulator
• Retinoblastoma

External links

• RB1 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• Retinoblastoma genes at the US National Library of Medicine Medical Subject Headings (MeSH)
• GeneReviews/NIH/NCBI/UW entry on Retinoblastoma
• Retinoblastoma Genetics
• Drosophila Retinoblastoma-family protein - The Interactive Fly
• Drosophila Retinoblastoma-family protein 2 - The Interactive Fly
• Evolutionary Homologs Retinoblastoma-family proteins - The Interactive Fly
• There is a diagram of the pRb-E2F interactions here.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.