Retinoblastoma protein

1AD6, 1GH6, 1GUX, 1H25, 1N4M, 1O9K, 1PJM, 2AZE, 2QDJ, 2R7G, 3N5U, 3POM, 4ELJ, 4ELL, 4CRI592519645ENSG00000139687ENSMUSG00000022105P06400P13405NM_000321NM_009029NP_000312NP_000312.2NP_033055The 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 Rb 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, Rb is phosphorylated to pRb, leading to the inactivation of the activity of Retinoblastoma protein. This process allows cells to enter into the cell cycle state. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.1ad6: DOMAIN A OF HUMAN RETINOBLASTOMA TUMOR SUPPRESSOR1gh6: RETINOBLASTOMA POCKET COMPLEXED WITH SV40 LARGE T ANTIGEN1gux: RB POCKET BOUND TO E7 LXCXE MOTIF1o9k: CRYSTAL STRUCTURE OF THE RETINOBLASTOMA TUMOUR SUPPRESSOR PROTEIN BOUND TO E2F PEPTIDE2aze: Structure of the Rb C-terminal domain bound to an E2F1-DP1 heterodimer 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 Rb 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, Rb is phosphorylated to pRb, leading to the inactivation of the activity of Retinoblastoma protein. This process allows cells to enter into the cell cycle state. 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. 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. RB1 orthologs have also been identified in most mammals for which complete genome data are available. RB/E2F-family proteins repress transcription. 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.