retinoblastoma protein retinoblastoma protein the retinoblastoma protein (protein name abbreviated rb; gene name abbreviated rb, rb or rb1) is a proto-oncogenic 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, inactivating it, and the cell cycle is allowed to progress. it is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases. rb1available structurespdbortholog search: pdbe rcsb list of pdb id codes1ad6, 1gh6, 1gux, 1h25, 1n4m, 1o9k, 1pjm, 2aze, 2qdj, 2r7g, 3n5u, 3pom, 4elj, 4ell, 4criidentifiersaliasesrb1, prb, rb, retinoblastoma 1, osrc, ppp1r130, p105-rb, pp110, retinoblastoma protein, rb transcriptional corepressor 1, p110-rb1external idsomim: 614041 mgi: 97874 homologene: 272 genecards: rb1 gene location (human)chr.chromosome 13 (human)band13q14.2start48,303,744 bpend48,599,436 bpgene location (mouse)chr.chromosome 14 (mouse)band14 38.73 cm|14 d3start73,421,113 bpend73,563,262 bprna expression patternbgeehumanmouse (ortholog)top expressed invisceral pleuragerminal epitheliumpalpebral conjunctivaparietal pleuraseminal vesiculabrodmann area 23cancellous bonejejunumjejunal mucosatibiatop expressed inmolarbloodhair folliclesecondary oocytecumulus cellsexually immature organismthymusbrown adipose tissuepineal glandganglionic eminencemore reference expression databiogpsmore reference expression datagene ontologymolecular function dna binding dna-binding transcription factor activity transcription coactivator activity transcription factor binding phosphoprotein binding kinase binding protein binding androgen receptor binding identical protein binding enzyme binding ubiquitin protein ligase binding importin-alpha family protein binding disordered domain specific binding cis-regulatory region sequence-specific dna binding dna-binding transcription repressor activity, rna polymerase ii-specific cellular component pml body swi/snf complex transcription regulator complex spindle cyclin/cdk positive transcription elongation factor complex chromatin nucleus nucleoplasm rb-e2f complex biological process negative regulation of cell population proliferation negative regulation of mitotic cell cycle neuron apoptotic process androgen receptor signaling pathway chromatin remodeling negative regulation of smoothened signaling pathway negative regulation of protein kinase activity cell morphogenesis involved in neuron differentiation mitotic cell cycle checkpoint signaling regulation of transcription by rna polymerase ii positive regulation of macrophage differentiation cellular response to xenobiotic stimulus negative regulation of cell cycle negative regulation of dna-binding transcription factor activity transcription, dna-templated glial cell apoptotic process regulation of cohesin loading regulation of cell cycle neuron maturation cell division positive regulation of transcription, dna-templated negative regulation of g1/s transition of mitotic cell cycle positive regulation of mitotic metaphase/anaphase transition regulation of centromere complex assembly enucleate erythrocyte differentiation neuron differentiation regulation of mitotic cell cycle negative regulation of epithelial cell proliferation skeletal muscle cell differentiation sister chromatid biorientation protein localization to chromosome, centromeric region cell cycle striated muscle cell differentiation ras protein signal transduction myoblast differentiation viral process negative regulation of transcription, dna-templated neuron projection development digestive tract development maintenance of mitotic sister chromatid cohesion regulation of lipid kinase activity positive regulation of transcription by rna polymerase ii hepatocyte apoptotic process apoptotic process positive regulation of transcription regulatory region dna binding negative regulation of gene expression regulation of cell growth tissue homeostasis regulation of transcription, dna-templated g1/s transition of mitotic cell cycle negative regulation of transcription by rna polymerase ii negative regulation of transcription involved in g1/s transition of mitotic cell cycle chromatin organization aortic valve morphogenesis negative regulation of inflammatory response positive regulation of extracellular matrix organization positive regulation of collagen fibril organization negative regulation of myofibroblast differentiation cell differentiation negative regulation of cold-induced thermogenesis negative regulation of protein serine/threonine kinase activity negative regulation of tau-protein kinase activity negative regulation of apoptotic signaling pathway sources:amigo / quickgoorthologsspecieshumanmouseentrez592519645ensemblensg00000139687ensmusg00000022105uniprotp06400p13405refseq (mrna)nm_000321nm_009029refseq (protein)np_000312np_000312.2np_033055location (ucsc)chr 13: 48.3 – 48.6 mbchr 14: 73.42 – 73.56 mbpubmed searchwikidataview/edit humanview/edit mouse prb 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 papillomavirus, 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. in adults, retinal cells are not sloughed off or replaced and are subjected to high levels of mutagenic uv radiation. if both alleles of this gene are mutated in a retinal cell, the protein is inactivated and the cells grows uncontrollably, resulting in development of retinoblastoma cancer, hence the "rb" in the name 'prb'. thus most prb knock-outs occur in retinal tissue when uv radiation-induced mutation inactivates all healthy copies of the gene, but prb knock-out has 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 over six times more likely to develop other types of cancer later in life, compared to individuals with sporadic retinoblastoma. this highlighted the fact that mutated prb could be inherited and lent support for 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 prb 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 prb 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 repress transcription. structure denotes function prb is a multifunctional protein with many binding and phosphorylation sites. although its common function is seen as binding and repressing e2f targets, prb is likely a multifunctional protein as it binds to at least 100 other proteins. prb has three major structural components: a carboxy-terminus, a "pocket" subunit, and an amino-terminus. within each domain, 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 prb'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 role of cdk4, cyklin d, rb and e2f in cell cycle regulation. prb 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. prb 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 prb-e2f/dp complex also attracts a histone deacetylase (hdac) protein to the chromatin, reducing transcription of s phase promoting factors, further suppressing dna synthesis. prb attenuates protein levels of known e2f targets prb has the ability to reversibly inhibit dna replication through transcriptional repression of dna replication factors. prb is able to bind to transcription factors in the e2f family and thereby inhibit their function. when prb is chronically activated, it leads to the downregulation of the necessary dna replication factors. within 72–96 hours of active prb 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 prb, cells treated with cisplatin, a dna-damaging agent, were able to continue proliferating, without cell cycle arrest, suggesting prb plays an important role in triggering chronic s-phase arrest in response to genotoxic stress. one such example of e2f-regulated genes repressed by prb 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, prb is able to inhibit the g1/s transition. repression mechanisms of e2fs 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. 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. e2f1 to e2f5 are known to associate with proteins in the prb-family of proteins while e2f6 and e2f7 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 e2f1, e2f2 and e2f3 while the repressor e2fs are e2f4, e2f5 and e2f6. activator e2fs along with e2f4 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. blocking of pre-initiation complex assembly 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 prb being recruited to the promoter as well as having a target present in tfiid. the presence of prb may change the conformation 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. modification of 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. prb interacts with the histone deacetylases hdac1 and hdac3. prb binds to hdac1 in its pocket domain in a region that is independent to its e2f-binding site. prb recruitment of histone deacetylases 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 prb to arrest cells in g1. to further add to this point, the hdac-prb complex is shown to be disrupted by cyclin d/cdk4 which levels increase and peak during the late g1 phase. senescence induced by prb senescence in cells is a state in which cells are metabolically active but are no longer able to replicate. prb is an important regulator of senescence in cells and since this prevents proliferation, senescence is an important antitumor mechanism. prb may occupy e2f-regulated promoters during senescence. for example, prb was detected on the cyclin a and pcna promoters in senescent cells. s-phase