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. The RB gene may have been responsible for the evolution of multicellularity in several lineages of life including animals.
Name and genetics
In humans, the protein is encoded by the RB1 gene located on chromosome 13—more specifically, 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.
RB/E2F-family proteins repress transcription.
Structure denotes function
Rb is a multifunctional protein with many binding and phosphorylation sites. Although its common function is seen as binding and repressing E2F targets, Rb is likely a multifunctional protein as it binds to at least 100 other proteins.
Rb has three major structural components: a carboxy-terminus, a “pocket” subunit, and an amino-terminus. Within each subunit, there are a variety of protein binding sites, as well as a total of 15 possible phosphorylation sites. Generally, phosphorylation causes interdomain locking, which changes Rb’s conformation and prevents binding to target proteins. Different sites may be phosphorylated at different times, giving rise to many possible conformations and likely many functions/ activity levels.
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 E2 promoter-binding–protein-dimerization partner (E2F-DP) dimers, which are transcription factors of the E2F family that push the cell into S phase. By keeping E2F-DP inactivated, RB1 maintains the cell in the G1 phase, preventing progression through the cell cycle and acting as a growth suppressor. 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.
Rb attenuates protein levels of known E2F Targets
Retinoblastoma protein (Rb) has the ability to reversibly inhibit DNA replication through transcriptional repression of DNA replication factors. Rb is able to bind to transcription factors in the E2F family and thereby inhibit their function. When Rb is chronically activated, it leads to the downregulation of the necessary DNA replication factors. Within 72–96 hours of active Rb induction in A2-4 cells, the target DNA replication factor proteins—MCMs, RPA34, DBF4, RFCp37, and RFCp140—all showed decreased levels. Along with decreased levels, there was a simultaneous and expected inhibition of DNA replication in these cells. This process, however, is reversible. Following induced knockout of Rb, cells treated with cisplatin, a DNA-damaging agent, were able to continue proliferating, without cell cycle arrest, suggesting Rb plays an important role in triggering chronic S-phase arrest in response to genotoxic stress.
One such example of E2F-regulated genes repressed by Rb are cyclin E and cyclin A. Both of these cyclins are able to bind to Cdk2 and facilitate entry into the S-phase of the cell cycle. Through the repression of expression of cyclin E and cyclin A, Rb is able to inhibit the G1/S transition.
Mechanisms of Repressed Transcription
There are at least three distinct mechanisms in which pRb can repress transcription of E2F-regulated promoters. Though these mechanisms are known, it is unclear which are the most important for the control of the cell cycle.
pRb binds to the activator domain of activator E2Fs
E2Fs are a family of proteins whose binding sites are often found in the promoter regions of genes for cell proliferation or progression of the cell cycle. E2F-1 to E2F-5 are known to associate with proteins in the pRb-family of proteins while E2F-6 and E2F-7 are independent of pRb. Broadly, the E2Fs are split into activator E2Fs and repressor E2Fs though their role is more flexible than that on occasion. The activator E2Fs are E2F-1, E2F-2 and E2F-3 while the repressor E2Fs are E2F-4, E2F-5 and E2F-6. Activator E2Fs along with E2F-4 bind exclusively to pRb. pRb is able to bind to the activation domain of the activator E2Fs which blocks their activity, repressing transcription of the genes controlled by that E2F-promoter.
pRb recruitment to a promoter blocks the assembly of pre-initiation complexes
The preinitiation complex (PIC) assembles in a stepwise fashion on the promoter of genes to initiate transcription. The TFIID binds to the TATA box in order to begin the assembly of the TFIIA, recruiting other transcription factors and components needed in the PIC. Data suggests that pRb is able to repress transcription by both Rb being recruited to the promoter as well as having a target present in TFIID.
The presence of pRb may change the confirmation of the TFIIA/IID complex into a less active version with a decreased binding affinity. pRb can also directly interfere with their association as proteins, preventing TFIIA/IID from forming an active complex.
pRb associates with complexes to modify chromatin structure
pRb acts as a recruiter that allows for the binding of proteins that alter chromatin structure onto the site E2F-regulated promoters. Access to these E2F-regulated promoters by transcriptional factors is blocked by the formation of nucleosomes and their further packing into chromatin. Nucleosome formation is regulated by post-translational modifications to histone tails. Acetylation leads to the disruption of nucleosome structure. Proteins called histone acetyltransferases (HATs) are responsible for acetylating histones and thus facilitating the association of transcription factors on DNA promoters. Deacetylation, on the other hand, leads to nucleosome formation and thus makes it more difficult for transcription factors to sit on promoters. Histone deacetylases (HDACs) are the proteins responsible for facilitating nucleosome formation and are therefore associated with transcriptional repressors proteins.
Rb interacts with the histone deactylases HDAC1, HDAC3, and HDAC3. Rb binds to HDAC1 in its pocket domain in a region that is independent to its E2F-binding site. Rb recruitment of histone deactylases leads to the repression of genes at E2F-regulated promoters due to nucleosome formation. Some genes activated during the G1/S transition such as cyclin E are repressed by HDAC during early to mid-G1 phase. This suggests that HDAC-assisted repression of cell cycle progression genes is crucial for the ability of Rb to arrest cells in G1. To further add to this point, the HDAC-Rb complex is shown to be disrupted by cyclin D/Cdk4 which levels increase and peak during the late G1 phase.
Senescence induced by Rb
Senescence in cells is a state in which cells are metabolically active but are no longer able to replicate. Rb is an important regulator of senescence in cells and since this prevents proliferation, senescence is an important antitumor mechanism. Rb may occupy E2F-regulated promoters during senescence. For example, Rb was detected on the cyclin A and PCNA promoters in senescent cells.
Premature Senescence and S-phase Arrest
Cells respond to stress in the form of DNA damage, activated oncogenes, or sub-par growing conditions, and can enter a senescence-like state called “premature senescence.” This allows the cell to prevent further replication during periods of damaged DNA or general unfavorable conditions. DNA damage in a cell can induce Rb activation. Rb’s role in repressing the transcription of cell cycle progression genes leads to the S-phase arrest that prevents replication of damaged DNA.
Activation and inactivation
When it is time for a cell to enter S phase, complexes of cyclin-dependent kinases (CDK) and cyclins phosphorylate Rb to pRb, allowing E2F-DP to dissociate from pRb and become active. When E2F is free it activates factors like cyclins (e.g. cyclin E and cyclin 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.
Since the 1990s, Rb was known to be inactivated via phosphorylation. Until, the prevailing model was that Cyclin D- Cdk 4/6 progressively phosphorylated it from its unphosphorylated to it hyperphosphorylated state (14+ phosphorylations). However, it was recently shown that Rb only exists in three state: un-phosphorylated, mono-phosphorylated, and hyper-phosphorylated. Each has a unique cellular function.
Before the development of 2D IEF, only hyper-phosphorylated Rb was distinguishable from all other forms, i.e. un-phosphorylated Rb resembled mono-phosphorylated Rb on immunoblots. As Rb was either in its active “hypo-phosphorylated” state or inactive “hyperphosphorylated” state. However, with 2D IEF, it is now known that Rb is un-phosphorylated in G0 cells and mono-phosphorylated in early G1 cells, prior to hyper-phosphorylation after the restriction point in late G1.
Cyclin D - Cdk 4/6 Mono-phosphorylates Rb
When a cell enters G1, Cyclin D- Cdk4/6 phosphorylates Rb at a single phosphorylation site. No progressive phosphorylation occurs because when HFF cells were exposed to sustained cyclin D- Cdk4/6 activity (and even deregulated activity) in early G1, only mono-phosphorylated Rb was detected. Furthermore, triple knockout, p16 addition, and Cdk 4/6 inhibitor addition experiments confirmed that Cyclin D- Cdk 4/6 is the sole phosphorylator of Rb.
Throughout early G1, mono-phosphorylated Rb exists as 14 different isoforms (the 15th phosphorylation site is not conserved in primates in which the experiments were performed). Together, these isoforms represent the “hypo-phosphorylated” active Rb state that was thought to exist. Each isoform has distinct E2F binding preferences which suggest that mono-phosphorylated Rb has a diversity of functions and can be “active” to varying degrees.It is currently unknown how such specificity is achieved.
Passing a bifurcation point induces hyper-phosphorylation by Cyclin E - Cdk2
After a cell passes the restriction point, Cyclin E - Cdk 2 hyper-phosphorylates all mono-phosphorylated isoforms. While the exact mechanism is unknown, one hypothesis is that binding to the C-terminus tail opens the pocket subunit, allowing access to all phosphorylation sites. This process is hysteretic and irreversible, and it is thought accumulation of mono-phosphorylated Rb induces the process. The bistable, switch like behavior of Rb can thus be modeled as a bifurcation point:
Un-phosphorylated and mono-phosphorylated Rb have unique functional roles
Presence of un-phosphorylated Rb drives cell cycle exit and maintains senescence. At the end of mitosis, PP1 dephosphorylates hyper-phosphorylated Rb directly to its un-phosphorylated state. Furthermore, when cycling C2C12 myoblast cells differentiated (by being placed into a differentiation medium), only un-phosphorylated Rb was present. Additionally, these cells had a markedly decreased growth rate and concentration of DNA replication factors (suggesting G0 arrest).
This function of un-phosphorylated Rb gives rise to a hypothesis for the lack of cell cycle control in cancerous cells: Deregulation of Cyclin D - Cdk 4/6 phosphorylates un-phosphorylated Rb in senescent cells to mono-phosphorylated Rb, causing them to enter G1. The mechanism of the switch for Cyclin E activation is not known, but one hypothesis is that it is a metabolic sensor. Mono-phosphorylated Rb induces an increase in metabolism, so the accumulation of mono-phosphorylated Rb in previously G0 cells then causes hyper-phosphorylation and mitotic entry. Since any un-phosphorylated Rb is immediately phosphorylated, the cell is then unable to exit the cell cycle, resulting in continuous division.
DNA damage to G0 cells activates Cyclin D - Cdk 4/6, resulting in mono-phosphorylation of un-phosphorylated Rb. Then, active mono-phosphorylated Rb causes repression of E2F-targeted genes specifically. Therefore, mono-phosphorylated Rb is thought to play an active role in DNA damage response, so that E2F gene repression occurs until the damage is fixed and the cell can pass the restriction point. As a side note, the discovery that damages causes Cyclin D - Cdk 4/6 activation even in G0 cells should be kept in mind when patients are treated with both DNA damaging chemotherapy and Cyclin D - Cdk 4/6 inhibitors.
Rb family proteins are components of the DREAM complex composed of DP, E2F4/5, RB-like (p130/p107) And MuvB (Lin9:Lin37:Lin52:RbAbP4:Lin54). The DREAM complex is assembled in Go/G1 and maintains quiescence by assembling at the promoters of > 800 cell-cycle genes and mediating transcriptional repression. Assembly of DREAM requires DYRK1A (Ser/Thr kinase) dependant phosphorylation of the MuvB core component, Lin52 at Serine28. This mechanism is crucial for recruitment of p130/p107 to the MuvB core and thus DREAM assembly.
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.
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.
Retinoblastoma protein has been shown to interact with:
- Abl gene
- Androgen receptor
- Apoptosis-antagonizing transcription factor
- Aryl hydrocarbon receptor
- Cyclin A1
- Cyclin D1
- Cyclin T2
- Histone deacetylase 2
- Peroxisome proliferator-activated receptor gamma
- Plasminogen activator inhibitor-2
- Polymerase (DNA directed), alpha 1
- Promyelocytic leukemia protein
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- 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[permanent dead link].