Retinoblastoma protein
The retinoblastoma protein (protein name abbreviated Rb; gene name abbreviated Rb, RB or RB1) is a tumor suppressor protein that is dysfunctional in several major cancers.[5] 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.[6]
"RB1" redirects here. For the automobile, see Red Bull RB1.pRb belongs to the pocket protein family, whose members have a pocket for the functional binding of other proteins.[7][8] 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.[9]
Name and genetics[edit]
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 in a retinal cell, the protein is inactivated and the cells grow 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.[10] 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.[11] 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[12] have also been identified in most mammals for which complete genome data are available.
RB/E2F-family proteins repress transcription.[13]
Structure denotes function[edit]
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.[14]
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.[15]
Consequences of pRb loss[edit]
Consequences of loss of pRb function is dependent on cell type and cell cycle status, as pRb's tumor suppressive role changes depending on the state and current identity of the cell.
In G0 quiescent stem cells, pRb is proposed to maintain G0 arrest although the mechanism remains largely unknown. Loss of pRb leads to exit from quiescence and an increase in the number of cells without loss of cell renewal capacity. In cycling progenitor cells, pRb plays a role at the G1, S, and G2 checkpoints and promotes differentiation. In differentiated cells, which make up the majority of cells in the body and are assumed to be in irreversible G0, pRb maintains both arrest and differentiation.[28]
Loss of pRb therefore exhibits multiple different responses within different cells that ultimately all could result in cancer phenotypes. For cancer initiation, loss of pRb may induce cell cycle re-entry in both quiescent and post-mitotic differentiated cells through dedifferentiation. In cancer progression, loss of pRb decreases the differentiating potential of cycling cells, increases chromosomal instability, prevents induction of cellular senescence, promotes angiogenesis, and increases metastatic potential.[28]
Although most cancers rely on glycolysis for energy production (Warburg effect),[29] cancers due to pRb loss tend to upregulate oxidative phosphorylation.[30] The increased oxidative phosphorylation can increase stemness, metastasis, and (when enough oxygen is available) cellular energy for anabolism.[30]
In vivo, it is still not entirely clear how and which cell types cancer initiation occurs with solely loss of pRb, but it is clear that the pRb pathway is altered in large number of human cancers.[110] In mice, loss of pRb is sufficient to initiate tumors of the pituitary and thyroid glands, and mechanisms of initiation for these hyperplasia are currently being investigated.[31]
As a drug target[edit]
pRb Reactivation[edit]
While the frequency of alterations of the RB gene is substantial for many human cancer types including as lung, esophageal, and liver, alterations in up-steam regulatory components of pRb such as CDK4 and CDK6 have been the main targets for potential therapeutics to treat cancers with dysregulation in the RB pathway.[34] This focus has resulted in the recent development and FDA clinical approval of three small molecule CDK4/6 inhibitors (Palbociclib (IBRANCE, Pfizer Inc. 2015), Ribociclib (KISQUALI, Novartis. 2017), and Abemaciclib (VERZENIO, Eli Lilly. 2017)) for the treatment of specific breast cancer subtypes. However, recent clinical studies finding limited efficacy, high toxicity, and acquired resistance[35][36] of these inhibitors suggests the need to further elucidate mechanisms that influence CDK4/6 activity as well as explore other potential targets downstream in the pRb pathway to reactivate pRb's tumor suppressive functions. Treatment of cancers by CDK4/6 inhibitors depends on the presence of pRb within the cell for therapeutic effect, limiting their usage only to cancers where RB is not mutated and pRb protein levels are not significantly depleted.[34]
Direct pRb reactivation in humans has not been achieved. However, in murine models, novel genetic methods have allowed for in vivo pRb reactivation experiments. pRb loss induced in mice with oncogenic KRAS-driven tumors of lung adenocarcinoma negates the requirement of MAPK signal amplification for progression to carcinoma and promotes loss of lineage commitment as well as accelerate the acquisition of metastatic competency. Reactivation of pRb in these mice rescues the tumors towards a less metastatic state, but does not completely stop tumor growth due to a proposed rewiring of MAPK pathway signaling, which suppresses pRb through a CDK-dependent mechanism.[37]
Pro-apoptotic effects of pRb loss[edit]
Besides trying to re-activate the tumor suppressive function of pRb, one other distinct approach to treat dysregulated pRb pathway cancers is to take advantage of certain cellular consequences induced by pRb loss. It has been shown that E2F stimulates expression of pro-apoptotic genes in addition to G1/S transition genes, however, cancer cells have developed defensive signaling pathways that protect themselves from death by deregulated E2F activity. Development of inhibitors of these protective pathways could thus be a synthetically lethal method to kill cancer cells with overactive E2F.[34]
In addition, it has been shown that the pro-apoptotic activity of p53 is restrained by the pRb pathway, such that pRb deficient tumor cells become sensitive to p53 mediated cell death. This opens the door to research of compounds that could activate p53 activity in these cancer cells and induce apoptosis and reduce cell proliferation.[34]
This article incorporates text from the United States National Library of Medicine, which is in the public domain.