Alternative titles; symbols
HGNC Approved Gene Symbol: RB1
SNOMEDCT: 19906005, 370967009;
Cytogenetic location: 13q14.2 Genomic coordinates (GRCh38): 13:48,303,751-48,481,890 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q14.2 | Bladder cancer, somatic | 109800 | 3 | |
| Osteosarcoma, somatic | 259500 | 3 | ||
| Retinoblastoma | 180200 | Autosomal dominant; Somatic mutation | 3 | |
| Retinoblastoma, trilateral | 180200 | Autosomal dominant; Somatic mutation | 3 | |
| Small cell cancer of the lung, somatic | 182280 | 3 |
Dryja et al. (1984) cloned DNA fragments from chromosome 13. Three of these identified RFLPs from region 13q12-q22, which contains the retinoblastoma (180200) 'locus.'
Friend et al. (1986) isolated a cDNA that detects a chromosomal segment having the properties of the gene at the retinoblastoma locus. The gene was found to be expressed in many tumor types, but no RNA transcript was found in retinoblastomas or osteosarcomas. The locus spanned at least 70 kb of DNA. Friend et al. (1986) started with a 1.5 kb DNA sequence which could detect deletions involving 13q14 in 3 of 37 retinoblastomas. They then used chromosome walking techniques to isolate and map 30 kb of surrounding genomic DNA. One of the single-copy fragments recognized a DNA sequence in the mouse genome and also in human chromosome 13. The conservation of this DNA sequence between mouse and humans suggested that the cloned fragment contained a coding exon of a gene. Therefore, they tested the ability of this fragment to hybridize to RNA derived from retinoblastoma cells and from human retinal cells. They found that indeed it recognized a 4.7-kb RNA transcript in the retinal cell line but that this transcript was not detectable in 4 retinoblastomas.
As outlined by Cavenee (1986), when the cDNA described by Friend et al. (1986) was used as a probe to screen RNA samples from different tumor types, it was shown to hybridize to all of those tested except retinoblastomas and retinoblastoma-associated osteosarcomas. Furthermore, use of this cDNA to analyze the genomic structure of its homologous locus in 50 retinoblastomas or associated osteosarcomas showed that about 30% had somatically altered genomic loci. These alterations took the form of fragments of altered mobility (suggesting gene rearrangements), underrepresented fragments (suggesting heterozygous deletions), and missing fragments (suggesting homozygous deletions). Since one of the homozygous deletions was entirely contained within the genomic locus homologous to the cDNA probe, it was suggested that this expressed gene was indeed the RB1 gene.
Dryja et al. (1986) isolated a cDNA fragment derived from human retinal mRNA that detected a locus within 13q14 that is often deleted in retinoblastoma.
Lee et al. (1987) prepared a rabbit antiserum against the RB protein studied by Horsthemke et al. (1987) and showed that it was present in all cell lines expressing normal RB mRNA but was not detected in 5 retinoblastoma cell lines. The RB protein can be metabolically labeled with (32)P-phosphoric acid, indicating that it is a phosphoprotein. Biochemical fractionation and immunofluorescence studies demonstrated that most of the protein is located in the nucleus. Furthermore, the protein was retained by and could be eluted from DNA-cellulose columns, suggesting a DNA binding activity.
A gene encoding a messenger RNA of 4.6 kb, located in the proximity of esterase D (133280), was identified by Lee et al. (1987) as the retinoblastoma susceptibility gene on the basis of chromosomal location, homozygous deletion, and tumor-specific alterations in expression. Transcription of the gene was abnormal in all of 6 retinoblastomas examined: in 2, mRNA was not detectable, whereas 4 others expressed variable quantities of the mRNA with decreased molecular size of about 4.0 kb. In contrast, full-length RB mRNA was present in human fetal retina and placenta, and in other tumors such as neuroblastoma and medulloblastoma. The sequence of cDNA clones indicated a hypothetical protein of 816 amino acids.
Whyte et al. (1988) demonstrated that a 105,000-Da cellular protein, which is one of the cellular targets implicated in the process of transformation by the adenovirus E1A proteins, is in fact the product of the RB1 gene. This interaction with the formation of a stable protein/protein complex was the first demonstration of a physical link between an oncogene and an antioncogene. A similar case can be made for numerous other disorders, many of which are more common.
Toguchida et al. (1993) reported the complete genomic sequence of the RB1 gene, which was contained in a 180,388-bp contig. The gene produces a 4.7-kb transcript that encodes a nuclear phosphoprotein consisting of 928 amino acids.
Hong et al. (1989) demonstrated that the RB transcript is encoded in 27 exons dispersed over about 200 kb of genomic DNA. The length of individual exons ranges from 31 to 1,889 bp. The largest intron spans more than 60 kb and the smallest one has only 80 bp. Deletion of exons 13-17 is frequently observed in various types of tumors, including retinoblastoma, breast cancer, and osteosarcoma, and the presence of a potential 'hotspot' for recombination in the region was predicted. A putative 'leucine-zipper' motif is exclusively encoded by exon 20. Transcription of RB is initiated at multiple positions and the sequences surrounding the initiation sites have a high G+C content. Several features of the RB promoter are reminiscent of those associated with many so-called housekeeping genes, consistent with the ubiquitous expression of the RB gene.
Stone et al. (1989) mapped the mouse homolog of the human retinoblastoma gene, symbolized Rb1, to chromosome 14 by analysis of somatic cell hybrids. In recombinant inbred strains, the findings suggested close linkage of Rb1 and Es10, which appears to be the mouse homolog of ESD (133280). By in situ hybridization, Ono and Yoshida (1993) assigned the RB1 gene to mouse 14D3 and the rat homolog to 15q12. A unique sequence human RB1 cosmid DNA probe was used by Verma et al. (1996) to localize the RB1 homolog in chimpanzee, gorilla, and orangutan to chromosome 14 by fluorescence in situ hybridization.
Analysis of the RB1 gene sequence by Toguchida et al. (1993) indicated a high ratio of (A+T)/(G+C) and a high density of Line-1 (L1) repeat sequences, suggesting that the gene maps to G-bands 13q14.12 or 13q14.2.
DeCaprio et al. (1989), Buchkovich et al. (1989), and Chen et al. (1989) demonstrated that the RB1 gene product has the properties of a cell cycle regulatory element and that its function is modulated by a phosphorylation/dephosphorylation mechanism during cell proliferation and differentiation. In G0/G1 cells, virtually all the RB protein is unphosphorylated, whereas during S and G2 phases, it is largely, if not exclusively, phosphorylated.
Shiio et al. (1992) found evidence that wildtype p53 suppresses transcription of the RB gene. From deletion and mutagenesis experiments, a cis-acting element (GGAAGTGA) susceptible to regulation by p53 was mapped within the RB promoter.
Mancini et al. (1994) demonstrated by immunoblotting and immunolabeling that a significant portion of hypophosphorylated Rb associates with the nuclear matrix during the early G1 phase. They suggested that Rb interactions with a nuclear matrix may be important for its ability to regulate cell cycle progression. Mutant Rb in tumor cells did not associate with the matrix, whereas Rb-reconstituted cells contained abundant matrix-bound Rb.
Weinberg (1995) reviewed the role of the RB protein in the control of the cell cycle.
Fearon (1997) provided a schematic representation of the cellular localization and presumed functions of the proteins encoded by inherited cancer genes.
Luo et al. (1998) demonstrated that Rb can repress transcription of endogenous cell cycle genes containing E2F sites through recruitment of histone deacetylase, which deacetylates histones on the promoter, thereby promoting formation of nucleosomes that inhibit transcription.
RB inhibits progression from G1 to S phase of the cell cycle and associates with a number of cellular proteins. Zhang et al. (1999) presented evidence that RB must normally interact with the E2F family of transcription factors to arrest cells in G1, and that this arrest results from active transcriptional repression by the RB-E2F complex, not from inactivation of E2F. Thus, a major role of E2F in cell cycle regulation is assembly of this repressor complex. Zhang et al. (1999) demonstrated that active repression by the RB-E2F complex mediates the G1 arrest triggered by transforming growth factor-beta (TGFB; 190180), p16(INK4A) (CDKN2A; 600160), and contact inhibition.
Harbour et al. (1999) presented evidence that phosphorylation of the C-terminal region of RB by CDK4 (123829)/CDK6 (603368) initiates successive intramolecular interactions between the C-terminal region and the central pocket. The initial interaction displaces histone deacetylase from the pocket, blocking active transcriptional repression by RB. This facilitates a second interaction that leads to phosphorylation of the pocket by CDK2 (116953) and disruption of pocket structure. These intramolecular interactions provide a molecular basis for sequential phosphorylation of RB by CDK4/CDK6 and CDK2. CDK4/CDK6 is activated early in G1, blocking active repression by RB. However, it is not until near the end of G1, when cyclin E (see 123837) is expressed and CDK2 is activated, that RB is prevented from binding and inactivating E2F.
Hsieh et al. (1999) showed that the binding of RB to MDM2 (164785) is essential for RB to overcome both the antiapoptotic function of MDM2 and the MDM2-dependent degradation of p53. Since RB specifically rescues the apoptotic function but not the transcriptional activity of p53 from negative regulation by MDM2, transactivation by wildtype p53 is not required for the apoptotic function of p53. These data demonstrated a role of RB in regulating the apoptotic function of p53.
Hanahan and Weinberg (2000) referred to deregulation of the retinoblastoma protein pathway as a 'hallmark of cancer.' In the absence of other genetic alterations, deregulation results in lack of differentiation, hyperproliferation, and apoptosis. The RB protein acts as a transcriptional repressor by targeting the E2F transcription factors (e.g., 189971), whose functions are required for entry into S phase. Increased E2F activity can induce S phase in quiescent cells; this is a central element of most models for the development of cancer. Lomazzi et al. (2002) showed that increased E2F1 activity can result in S phase entry in diploid fibroblasts only when the p53 (191170)-mediated G1 checkpoint is suppressed. They showed that E2F1 can induce S phase in primary mouse fibroblasts lacking Rb protein. These results indicated that in addition to acting as an E2F-dependent transcriptional repressor, RB protein is also required for the cells to retain the G1 checkpoint in response to unprogrammed proliferative signals.
Pennaneach et al. (2001) showed that the LxCxE-binding site in RB1 mediates both cell survival and cell cycle arrest after DNA damage. Replication factor C (RFC) complex plays an important role in DNA replication. Pennaneach et al. (2001) described a function of the large subunit of RFC, RFC1 (102579), in promoting cell survival after DNA damage. RFC1 contains an LxCxE motif, and mutation of this motif abolished the protective effect of RFC1. The inability of wildtype RFC1 to promote cell survival in RB1-null cells was rescued by RB1 but not by RB1 mutants defective in binding LxCxE proteins. RFC thus enhances cell survival after DNA damage in an RB1-dependent manner.
Nielsen et al. (2001) demonstrated that SUV39H1 (300254) and HP1 (604478) are both involved in the repressive functions of the retinoblastoma protein. Rb associates with SUV39H1 and HP1 in vivo by means of its pocket domain. SUV39H1 cooperates with Rb to repress the cyclin E (123837) promoter, and in fibroblasts that are disrupted for SUV39H1, the activity of the cyclin E and cyclin A2 (123835) genes are specifically elevated. Chromatin immunoprecipitation showed that Rb is necessary to direct methylation of histone H3, and is necessary for binding of HP1 to the cyclin E promoter. Nielsen et al. (2001) concluded that the SUV39H1-HP1 complex is not only involved in heterochromatic silencing but also has a role in repression of euchromatic genes by Rb and perhaps other corepressor proteins.
Dahiya et al. (2001) found that association between RB and Polycomb group (PcG; see 300227) proteins forms a repressor complex that blocks entry of cells into mitosis. Also, they provided evidence that RB colocalizes with nuclear PcG complexes and is important for association of PcG complexes with nuclear targets. The RB-PcG complex may provide a means to link cell cycle arrest to differentiation events leading to embryonic pattern formation.
The incidence of osteosarcoma is increased 500-fold in patients who inherit mutations in the RB gene. To understand why the RB protein is specifically targeted in osteosarcoma, Thomas et al. (2001) studied its function in osteogenesis. Loss of RB but not p107 (116957) or p130 (180203) blocked late osteoblast differentiation. RB physically interacted with the osteoblast transcription factor, CBFA1 (600211), and associated with osteoblast-specific promoters in vivo in a CBFA1-dependent fashion. Association of RB with CBFA1 and promoter sequences resulted in synergistic transactivation of an osteoblast-specific reporter. This transactivation function was lost in tumor-derived RB mutants, underscoring a potential role in tumor suppression. Thus, RB functions as a direct transcriptional coactivator promoting osteoblast differentiation, which may contribute to the targeting of RB in osteosarcoma.
By yeast 2-hybrid analysis using a human fibroblast cDNA library and protein pull-down assays with human EJ bladder cancer cells and Saos2 osteosarcoma cells, Leung et al. (2001) showed that MRG15 (MORF4L1; 607303) interacted with PAM14 (MRFAP1; 616905) and RB. Deletion analysis showed that the helix-loop-helix and leucine zipper regions of MRG15 were important for interaction with both PAM14 and RB. Immunoprecipitation analysis of EJ cells and human fibroblasts revealed that MRG15, PAM14, and RB were present in a multiprotein complex. Luciferase assays showed that MRG15 blocked RB-induced repression of the BMYB (MYBL2; 601415) promoter, leading to BMYB promoter activation. Leung et al. (2001) concluded that MRG15 regulates transcription through interactions with a complex containing RB and PAM14.
Using immunoprecipitation and immunoblot analyses, Tominaga et al. (2004) showed that Mrg15 interacted with Pam14 and Rb in mouse cells, similar to findings in human cells.
Fajas et al. (2002) found that Pparg (601487) promoted adipocyte differentiation more efficiently in Rb-deficient mouse embryonic fibroblasts than in Rb-expressing controls. Pparg and Rb coimmunoprecipitated, and the Pparg-Rb complex also contained histone deacetylase-3 (HDAC3; 605166). Rb recruited Hdac3 to the Pparg-Rb complex, and recruitment attenuated Pparg-mediated gene expression and adipocyte differentiation. Dissociation of the Pparg-Rb-Hdac3 complex by Rb phosphorylation or inhibition of Hdac activity stimulated adipocyte differentiation.
Chano et al. (2002) identified and cloned an RB1-inducible coiled-coil protein (RB1CC1; 606837) by differential display between a multidrug resistant osteosarcoma cell line and the sensitive parental cell line. By semiquantitative RT-PCR of a panel of cancer cell lines, they observed a close correlation between expression of RB1 and expression of RB1CC1. In addition, they found that exogenous expression of RB1CC1 in 2 leukemia cell lines produced a marked increase in RB1 expression. The induction was found to be due to the activation of the RB1 promoter by RB1CC1.
Garcia-Cao et al. (2002) reported a connection between members of the retinoblastoma family of proteins, RB1, RBL1 (116957), and RBL2 (180203), and the mechanisms that regulate telomere length. In particular, mouse embryonic fibroblasts doubly deficient in Rbl1 and Rbl2 or triply deficient in all 3 genes had markedly elongated telomeres compared with those of wildtype or Rb1-deficient cells. This deregulation of telomere length was not associated with increased telomerase (see 187270) activity. The abnormal elongated telomeres in doubly or triply deficient cells retained their end-capping function, as shown by the normal frequency of chromosomal fusions. These findings demonstrated a connection between the RB1 family and the control of telomere length in mammalian cells.
Brown and Gallie (2002) stated that interaction of mouse Rb with E2f on DNA is regulated by accumulation of phosphate groups in the C-terminal domain of Rb. By mutation analysis, they identified a 6-lysine basic patch in the Rb B domain that was necessary for release of Rb from E2f on DNA and for interaction of Rb with SV40 T antigen. Brown and Gallie (2002) suggested that release of E2F from Rb involves a conformational change whereby the C-terminal domain interacts with the B domain following phosphorylation by cyclin E.
Cellular senescence is a stable form of cell cycle arrest that limits proliferation of damaged cells and may act as a natural barrier to cancer progression. Narita et al. (2003) described a distinct heterochromatic structure that accumulates in senescent human fibroblasts, designated senescence-associated heterochromatic foci (SAHF). They found that SAHF formation coincides with recruitment of heterochromatin proteins and the RB1 protein to E2F-responsive promoters and is associated with the stable repression of E2F target genes. Both SAHF formation and the silencing of E2F target genes depended on the integrity of the RB pathway and did not occur in reversibly arrested cells.
The RB gene regulates proliferation, cell fate specification, and differentiation in the developing central nervous system. In the postnatal developing mouse retina, Zhang et al. (2004) found that Rb is expressed in proliferating retinal progenitor cells and differentiating rod photoreceptors. In retinal cell cultures from Rb-null mice and retinal cells from transgenic mice with targeted inactivation of the Rb gene, retinal progenitor cells continued to divide and rods did not mature, suggesting that Rb plays a role in cell proliferation and rod photoreceptor development.
Iavarone et al. (2004) showed that Rb-deficient embryos carry profound abnormalities of fetal liver macrophages that prevent physical interactions with erythroblasts. In contrast, wildtype macrophages bind Rb-deficient erythroblasts and lead to terminal differentiation and enucleation. Loss of Id2 (600386), a helix-loop-helix protein that mediates the lethality of Rb-deficient embryos, rescues the defects of Rb-deficient fetal liver macrophages. Rb promotes differentiation of macrophages by opposing the inhibitory functions of Id2 on the transcription factor PU.1 (165170), a master regulator of macrophage differentiation. Thus, Rb has a cell-autonomous function in fetal liver macrophages, and restrains Id2 in these cells to implement definitive erythropoiesis.
Sekimata and Homma (2004) developed a mouse myoblast cell line constitutively overexpressing Mizf (607099). When switched to differentiation medium, these cells showed decreased expression of Rb and several differentiation markers, and consequently could not differentiate into multinucleated myotubes. Sekimata and Homma (2004) concluded that repression of RB by MIZF is a critical determinant of myogenic differentiation.
Carreira et al. (2005) showed that cooperation between MITF (156845) and RB1 potentiates the ability of MITF to activate transcription. Carreira et al. (2005) suggested that MITF-mediated activation of p21(Cip1) (CDKN1A; 116899) expression and consequent hypophosphorylation of RB1 contributes to cell cycle exit and activation of the differentiation program.
Caenorhabditis elegans homologs of the Rb tumor suppressor complex specify cell lineage during development. Wang et al. (2005) showed that mutations in Rb pathway components enhanced RNA interference and caused somatic cells to express genes and elaborate perinuclear structures normally limited to germline-specific P granules. Furthermore, particular gene inactivations that disrupted RNA interference (RNAi) reversed the cell lineage transformations of Rb pathway mutants. Wang et al. (2005) concluded that mutations in Rb pathway components cause cells to revert to patterns of gene expression normally restricted to germ cells in C. elegans.
By profiling gene expression in developing mouse vestibular organs, Sage et al. (2005) identified the Rb protein as a candidate regulator of cell cycle exit in hair cells. Differentiated and functional mouse hair cells with a targeted deletion of Rb1 undergo mitosis, divide, and cycle, yet continue to become highly differentiated and functional. Moreover, acute loss of Rb1 in postnatal hair cells caused cell cycle reentry.
Using a yeast 2-hybrid screen to identify proteins that affect RB-mediated gene activation, Krutzfeldt et al. (2005) found that RFP (TRIM27; 602165) strongly reduced the effect of RB on glucocorticoid receptor (GCCR; 138040)-mediated transcription, but it did not prevent the ability of RB to inhibit E2F-mediated transcription. Mutation analysis showed that RFP interacted with the large pocket of RB in a manner distinct from that of E2F. Krutzfeldt et al. (2005) proposed that RFP expression may neutralize the RB-mediated differentiation response while leaving in place E2F-dependent cell cycle regulation and apoptosis protection.
Laurie et al. (2006) showed that the tumor surveillance pathway mediated by ARF (see 600160), MDM2 (164785), MDMX (602704), and p53 (191170) is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumor progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Laurie et al. (2006) concluded that their data provided evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, Laurie et al. (2006) suggested that their data supported the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma.
Williams et al. (2006) found that mouse fibroblasts lacking Rb were less susceptible to an oncogenic HRAS (190020) allele than wildtype cells. Depletion of RB from HRAS-transformed mouse cells or human tumor cells harboring HRAS pathway mutations inhibited their proliferation and anchorage-independent growth. In contrast to Rb -/- mouse fibroblasts, p107 -/- and p130 -/- fibroblasts were more susceptible to HRAS-mediated transformation than wildtype cells. Moreover, loss of RB in human tumor cells harboring an HRAS mutation resulted in increased expression of p107, and overexpression of p107, but not RB, strongly inhibited proliferation of these tumor cells. Williams et al. (2006) concluded that RB and p107 have distinct roles in HRAS-mediated transformation and that p107 has a role as a tumor suppressor in the context of activated HRAS.
Morris et al. (2008) demonstrated that E2F1 (189971) is a potent and specific inhibitor of beta-catenin (116806)/T cell factor (TCF)-dependent transcription and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses beta-catenin activity in an adenomatous polyposis coli (APC; 611731)/glycogen synthase kinase-3 (GSK3; see 606784)-independent manner, reducing the expression of key beta-catenin targets including c-MYC. This interaction explains why colorectal tumors, which depend on beta-catenin transcription for their abnormal proliferation, keep RB1 intact. Remarkably, E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8; 603184), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. Morris et al. (2008) concluded that thus, by retaining RB1 and amplifying CDK8, colorectal tumor cells select conditions that collectively suppress E2F1 and enhance the activity of beta-catenin.
Hume et al. (2008) showed that cytomegalovirus UL97 protein, like human cyclin-dependent kinases (see CDK2, 116953), phosphorylates RB, but does so in a cyclin-independent manner and is poorly inhibited by p21 (CDKN1A; 116899). Hume et al. (2008) concluded that UL97 is functionally orthologous to human CDK in phosphorylating RB but is immune from normal CDK control mechanisms.
Dgcr8 (609030)-knockout mouse embryonic stem (ES) cells lack microRNAs (miRNAs), proliferate slowly, and accumulate in G1 phase of the cell cycle. By screening mouse miRNAs for those that could rescue the growth defect in Dgcr8-knockout mouse ES cells, Wang et al. (2008) identified a group of related ES cell-specific miRNAs, including several members of the miR290 cluster. Target sites for these miRNAs were identified in the 3-prime UTRs of several inhibitors of the cyclin E-CDK2 pathway, including Cdkn1a, Rb1, Rbl1, Rbl2, and Lats2 (604861). Quantitative RT-PCR confirmed increased expression of these genes in Dgcr8-knockout mouse ES cells.
Wang et al. (2010) found that inactivation of Skp2 (601436), which is a target of Rb1, completely prevented spontaneous tumorigenesis in pituitaries of Rb1 +/- mice. Skp2 inactivation did not inhibit aberrant proliferation in Rb1-deleted melanotrophs but induced their apoptotic death. Elimination of p27 (600778) phosphorylation reproduced the effects of Skp2 knockout. Wang et al. (2010) concluded that downregulation of RB1 is tumorigenic due to unregulated SKP2-mediated ubiquitination of phosphorylated p27, followed by p27 degradation and cell cycle progression.
Depending on the differentiation factor and cellular context, the Rb protein can either suppress or promote the transcriptional activity of several master differentiation inducers. For example, Rb protein binds to RUNX2 (600211) and potentiates its ability to promote osteogenic differentiation in vitro. In contrast, Rb protein acts with E2F to suppress PPARG (601487), the master activator of adipogenesis. Because osteoblasts and adipocytes can both arise from mesenchymal stem cells, these observations suggest that Rb protein might play a role in the choice between these 2 fates. Calo et al. (2010) used mouse models to address this hypothesis in mesenchymal tissue development and tumorigenesis and showed that Rb status plays a key role in establishing fate choice between bone and brown adipose tissue in vivo.
Based on genomewide methylation analysis of a patient with multiple imprinting defects, Kanber et al. (2009) identified a differentially methylated CpG island in intron 2 of the RB1 gene. The CpG island is part of a 5-prime truncated, processed pseudogene derived from the KIAA0649 gene (614056) on chromosome 9 and corresponds to 2 small CpG islands in the open reading frame of the ancestral gene. It is methylated on the maternal chromosome 13 and acts as a weak promoter for an alternative RB1 transcript on the paternal chromosome 13. In 4 other KIAA0649 pseudogene copies, which are located on chromosome 22, the 2 CpG islands have deteriorated and the CpG dinucleotides are fully methylated. By analyzing allelic RB1 transcript levels in blood cells, as well as in hypermethylated and 5-aza-2-prime-deoxycytidine-treated lymphoblastoid cells, Kanber et al. (2009) found that differential methylation of the CpG island (CpG 85) skews RB1 gene expression in favor of the maternal allele. Thus, Kanber et al. (2009) concluded that RB1 is imprinted in the same direction as CDKN1C (600856), which operates upstream of RB1. The imprinting of 2 components of the same pathway indicates that there has been strong evolutionary selection for maternal inhibition of cell proliferation.
Xu et al. (2014) showed that postmitotic human cone precursors are uniquely sensitive to RB depletion. RB knockdown induced cone precursor proliferation in prospectively isolated populations and in intact retina. Proliferation followed the induction of E2F-regulated genes, and depended on factors having strong expression in maturing cone precursors and crucial roles in retinoblastoma cell proliferation, including MYCN (164840) and MDM2 (164785). Proliferation of RB-depleted cones and retinoblastoma cells also depended on the RB-related protein p107 (RBL1; 116957), SKP2 (601436), and a p27 (CDKN1B; 600778) downregulation associated with cone precursor maturation. Moreover, RB-depleted cone precursors formed tumors in orthotopic xenografts with histologic features and protein expression typical of human retinoblastoma. Xu et al. (2014) concluded that these findings provide a compelling molecular rationale for a cone precursor origin of retinoblastoma.
In mice, Walter et al. (2019) modeled RB loss during lung adenocarcinoma progression and pathway reactivation in established oncogenic KRAS (190070)-driven tumors. They showed that RB loss enables cancer cells to bypass 2 distinct barriers during tumor progression. First, RB loss abrogates the requirement for amplification of the mitogen-activated protein kinase (MAPK; see 176948) signal during malignant progression. Walter et al. (2019) identified CDK2 (116953)-dependent phosphorylation of RB as an effector of MAPK signaling and critical mediator of resistance to inhibition of CDK4 (123829) and CDK6 (603368). Second, RB inactivation deregulates the expression of cell-state-determining factors, facilitates lineage infidelity, and accelerates the acquisition of metastatic competency. By contrast, reactivation of RB reprograms advanced tumors towards a less metastatic cell state, but is nevertheless unable to halt cancer cell proliferation and tumor growth due to adaptive rewiring of MAPK pathway signaling, which restores a CDK-dependent suppression of RB.
Zatulovskiy et al. (2020) showed that cell growth during G1 phase of the cell division cycle diluted RB to trigger division in human cells. RB overexpression increased cell size and G1 duration, whereas RB deletion decreased cell size and removed the inverse correlation between cell size at birth and duration of G1 phase. Zatulovskiy et al. (2020) concluded that RB dilution through cell growth in G1 provides a molecular mechanism that promotes cell size homeostasis.
The restriction (R) point marks the point in the cell cycle when cells become independent of mitogen signaling and CDK2 activity becomes self-sustaining through a feedback loop between cyclin A2/CDK2 and RB1, leading to an irreversible commitment to proliferation. Cornwell et al. (2023) demonstrated that mitogen signaling maintained CDK2 activity in S and G2 phases of the cell cycle, and that, in the absence of mitogen signaling, some post-R-point cells exited the cell cycle and entered a G0-like state instead of irreversibly committing to proliferation. Further analysis indicated that mitosis and cell cycle exit were 2 mutually exclusive fates, and that competition between the 2 determined whether cells continued to proliferate or exited the cell cycle. As a result, the decision to proliferate was fully reversible, even when cells were in post-R state, because CDK2 activation and RB1 phosphorylation were reversible in all post-R cells after loss of mitogen signaling. CDK4/CDK6 promoted cyclin A2 synthesis in S/G2, and cyclin A2 stability was the primary contributor to cell cycle exit. Cells were dependent on mitogens and CDK4/CDK6 activity to maintain CDK2 activity and RB1 phosphorylation throughout the cell cycle. The R-point irreversibility phenomenon was observed in the absence of mitogens, because in most cells, the half-life of cyclin A2 was long enough to sustain CDK2 activity throughout G2/M to reach mitosis. The results implied that there is no single point when cells are irreversibly committed to proliferation that can be defined by a single molecular event, but rather that it is determined by the cell's proximity to mitosis, as well as the cyclin A2 level when mitogen signaling is lost.
Sivakumaran et al. (2005) conducted a comprehensive survey of sequence variation in the RB1 gene in diverse human populations and primates. A study of a wide range of ethnicities and 5 primate species indicated that nucleotide diversity of the coding region was 52 times lower than that of the noncoding regions, indicative of significant sequence conservation. The occurrence of purifying selection was corroborated by phylogeny-based maximum likelihood analysis of the RB1 sequences of human and 5 primates. RB1 displayed extensive linkage disequilibrium over 174 kb, and only 4 unique recombination events, 2 in Africa and 1 each in Europe and Southwest Asia, were observed.
Retinoblastoma
Fung et al. (1987) used a cDNA probe to determine the lesion in retinoblastomas (180200). In 16 of 40 retinoblastomas studied with a cDNA probe by Fung et al. (1987), a structural change in the RB gene was identifiable, including, in some cases, homozygous internal deletions with corresponding truncated transcripts. An osteosarcoma also had a homozygous internal deletion with a truncated transcript. Possible hotspots for deletion were identified within the RB genomic locus.
Bookstein et al. (1988) identified at least 20 exons in genomic clones of the RB gene and provisionally numbered them. With a unique sequence probe from intron 1, they detected heterozygous deletions in genomic DNA from 3 retinoblastoma cell lines and genomic rearrangements in fibroblasts from 2 hereditary retinoblastoma patients, indicating that intron 1 includes a frequent site for mutations conferring predisposition to retinoblastoma. Demonstration of a DNA deletion of exons 2-6 from 1 RB allele, as well as the demonstration of other deletions, explains the origin of shortened RB mRNA transcripts.
Dunn et al. (1989) extended the characterization of mutations in RB1 using RNase protection of RB1 transcripts to locate probable mutations, followed by polymerase chain reaction (PCR) to amplify and sequence the mutant allele. Mutations were identified in 15 of 21 RB tumors; in 8 tumors, the precise error in nucleotide sequence was characterized. Each of 4 germline mutations involved a small deletion or duplication while 3 somatic mutations were point mutations leading to splice alterations and loss of an exon from the mature RB1 mRNA.
By PCR techniques, Yandell et al. (1989) demonstrated single nucleotide changes in tumors from 7 patients with simplex retinoblastoma (with no family history of the disease). In 4 patients, the mutation involved only the tumor cells, and in 3 it involved normal somatic cells as well as tumor cells but was not found in either parent. Thus, these 3 represent new germinal mutations. All 3 were C-to-T transitions in the coding strand in the retinoblastoma gene. Two of the 3 occurred at CpG pairs.
Lohmann et al. (1996) studied 119 patients with hereditary retinoblastoma for germline RB1 mutations. Southern blot hybridization and PCR fragment-length analysis revealed mutations in 48 patients. In the remaining 71 patients, they detected mutations in 51 (72%) by applying heteroduplex analysis, nonisotopic SSCP, and direct sequencing. Rare sequence variants were also found in 4 patients. No region of the RB1 gene was preferentially involved in single base substitutions. Recurrent transitions were observed at most of the 14 CGA codons within the RB1 gene. No mutation was observed in exons 25-27, although this region contains 2 CGA codons. This suggested to the authors that mutations within the 3-prime terminal region of the RB1 gene may not be oncogenic. For the entire series of 119 patients, mutations were identified in 99 (83%). The spectrum comprised 15% large deletions, 26% small length alterations, and 42% base substitutions.
Harbour (2001) stated that recent advances in understanding of the structure and function of the RB protein provided insights into the molecular basis of low-penetrance retinoblastoma. Low-penetrance retinoblastoma mutations either cause a reduction in the amount of normal RB that is produced (class 1 mutations) or result in a partially functional mutant RB (class 2 mutations).
Sampieri et al. (2006) identified mutations in the RB1 gene in 13 (37%) of 35 unrelated Italian patients with retinoblastoma. Mutations were identified in 6 of 9 familial cases and 7 of 26 sporadic cases. Eleven of the 13 mutations were novel.
Zhang et al. (2012) showed that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss in retinoblastoma, Zhang et al. (2012) performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. Zhang et al. (2012) then evaluated the role of RB1 in genome stability and considered nongenetic mechanisms of cancer pathway deregulation. For example, the protooncogene SYK (600085) is upregulated in retinoblastoma and is required for tumor cell survival. Targeting SYK with a small molecule inhibitor induced retinoblastoma tumor cell death in vitro and in vivo. Thus, Zhang et al. (2012) concluded that retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.
Small-Cell Lung Cancer
Yokota et al. (1988) found markedly reduced amounts of RB transcript in some small-cell carcinomas (182280).
Hensel et al. (1988) found that all 3 patients with retinoblastoma whose DNA was heterozygous for a RFLP detected by an RB1 probe showed loss of 1 allele in DNA from small-cell lung cancer tissue.
Harbour et al. (1988) found structural abnormalities of the RB gene in 1 of 8 primary small-cell lung cancer tumors, in 4 of 22 small-cell lung cancer cell lines, and in 1 of 4 pulmonary carcinoid lines. RB mRNA was absent in 60% of SCLC lines and in 75% of pulmonary carcinoid lines, including all samples with DNA abnormalities. In contrast, RB transcripts were found in 90% of non-SCLC lines and in all normal human lung. It is of interest that both SCLC and pulmonary carcinoids are neuroendocrine tumors.
Horowitz et al. (1990) found that inactivation of the retinoblastoma protein, which is universal in retinoblastoma cells, is present in most small-cell lung cancers and in one-third of bladder cancers but is infrequent in other human tumors.
Metastatic Cancer
Robinson et al. (2017) performed whole-exome and transcriptome sequencing of 500 adult patients with metastatic solid tumors of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53 (191170), CDKN2A (600160), PTEN (601728), PIK3CA (171834), and RB1. Putative pathogenic germline variants were present in 12.2% of cases, of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling.
In a tumor from a patient (RB-2) with bilateral retinoblastoma (180200), Yandell et al. (1989) identified heterozygosity for a 1-bp deletion (2657delG) in exon 24 (which codes for amino acid 840) in the RB1 gene, which caused a frameshift and a new stop codon in exon 25. This was a somatic mutation.
In a tumor from a patient (RB-88) with unilateral retinoblastoma (180200), Yandell et al. (1989) identified a change of GT-to-GC at the first 2 nucleotides in the intron following exon 19 in the RB1 gene. Loss of the splice-donor site prevented normal splicing. The mutation was not found in the leukocytes of the patient or in the parents.
In the tumor of a patient (RB-74) with bilateral retinoblastoma (180200), Yandell et al. (1989) identified heterozygosity for a C-to-T transition at basepair 1462 in exon 14 of the RB1 gene, resulting in an arg445-to-ter substitution. This was a de novo germline mutation.
In the tumor from a patient (RB-104) with bilateral retinoblastoma (180200), Yandell et al. (1989) identified a 1838C-T transition in exon 18 of the RB1 gene, resulting in a ser567-to-leu substitution. This represented homozygosity for a new germline mutation.
In the tumor of a patient (RB-53) with bilateral retinoblastoma (180200), Yandell et al. (1989) identified a heterozygous 2498C-T transition in exon 23 of the RB1 gene, resulting in an arg787-to-ter substitution. This represented a new germline mutation.
In the tumor of a patient (RB-45) with unilateral retinoblastoma (180200), Yandell et al. (1989) identified a 1-bp deletion (2381delG) in exon 22 of the RB1 gene, which led to a frameshift and creation of a new stop codon close by in exon 22. This was a somatic mutation present in heterozygous state in the tumor.
In the tumor from a patient (RB-119) with retinoblastoma (180200), Yandell et al. (1989) identified a G-to-T transversion in the first nucleotide in the intron following exon 10, which led to loss of a splice/donor site and prevented normal splicing. The mutation was somatic and heterozygous in the tumor.
In cell line RB-W24 from a patient with retinoblastoma (180200), Yandell et al. (1989) identified a 1119C-T transition in exon 11 of the RB1 gene, resulting in an arg358-to-ter substitution. Yandell et al. (1989) could not characterize this mutation because normal somatic tissue was not available for study.
In a bladder cancer (109800) tumor designated J82, Horowitz et al. (1989) found an A-to-G transition in the next to the last nucleotide in the intron 5-prime to exon 21 in the RB1 gene. Loss of splice-acceptor site prevented normal splicing.
In a small-cell lung cancer tumor (182280) designated H69, Yandell et al. (1989) identified a 2379G-T transversion in exon 22 of the RB1 gene, resulting in a glu748-to-ter substitution.
In 2 unrelated patients with unilateral and unifocal retinoblastoma (RB571, RB600) (180200), Dunn et al. (1989) found identical somatic point mutations resulting in loss of exon 12. A frameshift introduced by the loss of exon 12 resulted in a truncated protein of 379 amino acids. A G-to-A transition at the splice donor site of exon 12 was responsible for aberrant splicing.
By RNase protection of the RB1 mRNA and sequencing of the PCR-cDNA in a patient (RB429) with bilateral retinoblastoma (180200). Dunn et al. (1989) identified a mutation in the RB1 gene: a 5-bp deletion in exon 8 causing a frameshift and a new termination codon in exon 8. The predicted truncated protein would contain 268 amino acids. Dunn et al. (1989) could not confirm that this was a germline mutation because constitutional cells from the patient were not available for study.
In the tumor of a patient (RB538) with retinoblastoma (180200), Dunn et al. (1989) identified a 55-bp duplication within exon 10 of the RB1 gene. A frameshift resulted in a new termination codon at position 346. This was a germline mutation.
In the tumor of a patient (RB543) with retinoblastoma (180200), Dunn et al. (1989) identified a 10-bp deletion within exon 18 of the RB1 gene, causing a frameshift and a new termination codon. The predicted truncated protein would contain 586 amino acids. This was a germline mutation.
In tumor RB470B from a patient (RB570) with retinoblastoma (180200), Dunn et al. (1989) demonstrated a 9-bp deletion in exon 19 of the RB1 gene, leading to a TAA termination codon. The predicted truncated protein would have 649 amino acids. This was a germline mutation. Different somatic mutations (614041.0016) were identified in 4 different tumors from this patient.
In patient RB570 with bilateral retinoblastoma who carried a 9-bp deletion in exon 19 of the RB1 gene as the germline mutation (614041.0015), Dunn et al. (1989) found a different somatic mutation in each of 4 separate tumors studied. These were 2 different LOH ('loss of heterozygosity') mutations, as indicated by RFLP studies, deletion of exon 22, and a tumor in which the exact nature of the change was not determined.
Sakai et al. (1991) identified 2 mutations in the 5-prime region of the RB gene in patients with retinoblastoma (180200). One was a G-to-T transversion 189 bp 5-prime to the initiating methionine codon; the second was a G-to-A transition 198 bp upstream of the initiating methionine codon (614041.0018). The penetrance of these mutations appeared to be low; both carriers in 1 family had only unilateral retinoblastoma, and there were at least 3 obligate carriers who had no retinoblastoma in the second family. The mutation in the first family was within a sequence homologous to the consensus sequence for ATF, a transcription factor related or identical to CREB1 (123810). The second mutation was within a sequence similar to that recognized by SP1 (189906), a transcription factor with a zinc finger DNA-binding domain. Sakai et al. (1991) demonstrated that these natural mutants did not bind the transcription factors mentioned. The incomplete penetrance of the mutations may be related to the fact that the mutations result in a quantitative decrease in the expression of the RB gene, rather than in its complete inactivity. To develop into a retinoblastoma, it may be necessary for the retinal cell carrying one of these mutations to acquire a second, complete loss-of-function mutation of the homologous normal allele.
See 614041.0017 and Sakai et al. (1991).
In 2 families with an unusual low-penetrance phenotype of retinoblastoma (180200), with many individuals carrying the gene being unaffected, unilaterally affected, or with evidence of spontaneously regressed tumors, Onadim et al. (1992) found mutations in exon 20 of RB1. (Also see 614041.0020.) In 1 family, a C-to-T transition in codon 661 converted an arginine (CGG) to tryptophan (TGG) codon. The incomplete penetrance might indicate that this single amino acid change modified protein structure/function such that tumorigenesis was not inevitable.
Cowell and Bia (1998) pointed out that Lohmann et al. (1994) identified the same codon-661 mutation in 2 families with low penetrance. Cowell and Bia (1998) referred to their unpublished observations, identifying the same mutation in another family where both the 2 affected children and the unaffected father carried the arg661-to-trp (R661W) mutation.
Otterson et al. (1999) stated that 9 families with incomplete penetrance of familial retinoblastoma and carrying a R661W mutation had been reported. Their studies of this mutation demonstrated that the mutation is temperature-sensitive.
See 614041.0019. In a second family with incomplete penetrance of retinoblastoma (180200), Onadim et al. (1992) observed a G-to-T transversion in codon 675 that converted a glutamine (GAA) to a stop (TAA) codon. The mutation occurred near a potential cryptic splice acceptor site, raising the possibility of alternative splicing resulting in a less severely disrupted protein.
Schubert et al. (1997) found a splicing mutation in a family with incomplete penetrance and variable expressivity of retinoblastoma (180200) as manifested by relatively late onset, unilaterality, and occurrence of unaffected carriers. Two RB1 cDNA products were identified by PCR: the wildtype product and a mutant cDNA that lacked exon 21. Sequence analysis of genomic DNA demonstrated a G-to-A transition at the last base of exon 21. The mutant allele did not change the amino acid code; both GAG and GAA encode glu. However, the alteration reduced the match of the exon boundary splice site to the consensus. Studies indicated that the mutation severely reduced correct splicing of the mutant mRNA but did not eliminate it.
In a child with ectopic intracranial retinoblastoma, Onadim et al. (1997) found a nonsense mutation in exon 17 (codon 556) of the RB1 gene in homozygous (or hemizygous) state in both the retinal and the pineal tumors (180200). Diagnosis of bilateral retinoblastoma was made at the age of 13 months; the patient presented with the pineal tumor 32 months after the initial diagnosis of retinoblastoma. The RB1 mutation was a C-to-T transition (CGA to TGA) within a CpG dinucleotide, converting an arginine codon to a stop codon (R556X). The mutation occurred in a region of the gene that codes for part of the 'pocket' region of the Rb protein. The mutation was present heterozygously in the DNA from the constitutional cells of the patient. The mutation was absent in the blood DNA of both the father and the mother, and was shown to have occurred on the copy of the RB1 gene derived from the father. This mutation had been reported by Hogg et al. (1993) in the retinal tumor from a unilateral nonhereditary case of retinoblastoma. The same mutation was identified as a germline mutation by Cowell et al. (1994) and Liu et al. (1995).
Lohmann et al. (1994) described a germline del480 RB1 mutation (in-frame deletion of RB1 codon 480, resulting from a triplet nucleotide deletion) in affected members in a pedigree with retinoblastoma (180200) showing incomplete penetrance. Otterson et al. (1999) demonstrated that this mutation is temperature-sensitive. The disease-eye ratio (DER) score for this family was 1.0, with 5 obligate carriers: 1 unaffected, 3 with unilateral disease, and 1 with bilateral disease.
In 2 separate previously reported families with incomplete penetrance of retinoblastoma (180200) and a cys712-to-arg (C712R) missense mutation in the RB1 gene, Otterson et al. (1999) found that the mutation was temperature-sensitive.
In 2 unrelated families with incomplete penetrance of retinoblastoma (180200), Klutz et al. (2002) found an IVS6+1G-T splice site mutation in the RB1 gene. Analysis of RNA from white blood cells showed that this mutation causes skipping of exon 6. Although the deletion resulted in a frameshift, most carriers of the mutation did not develop retinoblastoma. The relative abundance of the resultant nonsense mRNA varied between members of the same family and was either similar to or considerably lower than the transcript level of the normal allele.
De Jong et al. (2006) described the documented growth, clinical course, and histopathology of retinoblastomas (180200) in an untreated and otherwise normal right eye of a 27-year-old white male with a g.153211T-A (tyr606-to-ter; W606X) mutation in the RB1 gene, whose left eye had been enucleated at age 2 years for 2 retinoblastomas. Despite extensive treatment, the right eye had to be removed due to tumor recurrences and seeding, pseudohypopyon, and elevated intraocular pressure.
In a large family with incomplete penetrance of retinoblastoma (180200), Sanchez-Sanchez et al. (2007) identified a 23-bp duplication in exon 1 of the RB1 gene, resulting in a frameshift and premature termination in exon 2. Only 3 (30%) of 10 mutation carriers were affected by disease. RT-PCR analysis showed that the mutation did not induce nonsense-mediated decay. Transcript expression in cultured cells showed that downstream alternative in-frame translation sites involving met113 and possibly met223 were used to generate N-terminal truncated RB1 products known and suspected to exhibit tumor suppressor activity. The findings suggested that modulation of disease penetrance in this family was achieved by internal translation initiation.
In 2 brothers with retinoblastoma (180200) diagnosed at age 2 years, Dehainault et al. (2007) identified a -1398A-G transition in intron 23 of the RB1 gene (IVS23AS-1398A-G), resulting in a 103-bp insertion between exons 23 and 24. In silico analysis demonstrated the creation of a cryptic splice site leading to an intronic sequence exonization. The unaffected father also carried the mutation, likely in a mosaic state. The mutation was not identified by point mutation or large rearrangement screening and was only detected by complete transcript analysis using RNA extracted from the patients' lymphoblastoid cells treated with puromycin.
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