Gene Summary

Gene:PRB2; proline rich protein BstNI subfamily 2
Aliases: Ps, cP7, IB-9, PRPPRB1
Summary:This gene encodes a member of the heterogeneous family of basic, proline-rich, human salivary glycoproteins. The encoded preproprotein undergoes proteolytic processing to generate one or more mature isoforms before secretion from the parotid glands. Multiple alleles of this gene exhibiting variations in the length of the tandem repeats, polymorphic cleavage sites and polymorphic stop codons have been identified. This gene is located in a cluster of closely related salivary proline-rich proteins on chromosome 12. [provided by RefSeq, Oct 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:basic salivary proline-rich protein 2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Tumor Suppressor Gene
  • S Phase
  • Epigenetics
  • Cancer Gene Expression Regulation
  • Proteins
  • Retinoblastoma
  • Nuclear Proteins
  • Gene Expression Profiling
  • E2F Transcription Factors
  • Retinal Neoplasms
  • Chromosome 12
  • Cervical Cancer
  • Lung Cancer
  • Survival Rate
  • RB1
  • Genome-Wide Association Study
  • Single Nucleotide Polymorphism
  • Promoter Regions
  • Breast Cancer
  • Urinary Tract
  • Tumor Virus Infections
  • Transcription Factors
  • Cell Differentiation
  • Cancer DNA
  • Mutation
  • Cell Cycle
  • DNA Methylation
  • Multigene Family
  • Retinoblastoma-Like Protein p130
  • Immunohistochemistry
  • tat Gene Products, Human Immunodeficiency Virus
  • Urinary System Cancers
  • RBL1
  • Genetic Predisposition
  • Phosphoproteins
  • Transfection
  • p53 Protein
  • Genes, Retinoblastoma
  • PRB2
  • Cell Cycle Proteins
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PRB2 (cancer-related)

Michailidou K, Lindström S, Dennis J, et al.
Association analysis identifies 65 new breast cancer risk loci.
Nature. 2017; 551(7678):92-94 [PubMed] Free Access to Full Article Related Publications
Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10

Law PJ, Berndt SI, Speedy HE, et al.
Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia.
Nat Commun. 2017; 8:14175 [PubMed] Free Access to Full Article Related Publications
Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10

Tanaka S, Suzuki K, Sakaguchi M
The prolyl oligopeptidase inhibitor SUAM-14746 attenuates the proliferation of human breast cancer cell lines in vitro.
Breast Cancer. 2017; 24(5):658-666 [PubMed] Related Publications
BACKGROUND: Prolyl oligopeptidase (POP, EC is a serine peptidase that hydrolyzes post-proline peptide bonds in peptides that are <30 amino acids in length. We previously reported that POP inhibition suppressed the growth of NB-1 human neuroblastomas cells and KATO III human gastric cancer cells. POP activity is commonly elevated in many cancers, which includes breast cancer. However, the effect of POP inhibition as a candidate breast cancer therapy is unknown.
METHODS: The effects of POP inhibition and knockdown on the proliferation of cultured human estrogen receptor-positive (ER+) MCF7 and T47D, and ER-negative (ER-) MDA-MB-231 breast cancer cell lines and the MCF12A non-tumorigenic epithelial cell line were tested by analyzing their influence on cell proliferation (WST-1 assay), cell viability (trypan blue exclusion assay), and cell cycle arrest (cell cycle analysis, cell cycle regulator proteins expression).
RESULTS: POP-specific inhibitors 3-({4-[2-(E)-styrylphenoxy]butanoyl}-L-4-hydroxyprolyl)-thiazolidine (SUAM-14746) and benzyloxycarbonyl-thiopropyl-thioprolinal and RNAi-mediated POP knockdown inhibited the proliferation of MCF7 cells without inducing cell death. SUAM-14746-induced growth inhibition was also observed in T47D and MDA-MB-231 cells, but not in MCF12A cells. This growth inhibition was associated with G
CONCLUSIONS: SUAM-14746 inhibited breast cancer cell growth in a cytostatic manner without inducing lethality, and POP-specific inhibitors may be an effective treatment against ER+ and ER- breast cancer.

Salavert F, Hidago MR, Amadoz A, et al.
Actionable pathways: interactive discovery of therapeutic targets using signaling pathway models.
Nucleic Acids Res. 2016; 44(W1):W212-6 [PubMed] Free Access to Full Article Related Publications
The discovery of actionable targets is crucial for targeted therapies and is also a constituent part of the drug discovery process. The success of an intervention over a target depends critically on its contribution, within the complex network of gene interactions, to the cellular processes responsible for disease progression or therapeutic response. Here we present PathAct, a web server that predicts the effect that interventions over genes (inhibitions or activations that simulate knock-outs, drug treatments or over-expressions) can have over signal transmission within signaling pathways and, ultimately, over the cell functionalities triggered by them. PathAct implements an advanced graphical interface that provides a unique interactive working environment in which the suitability of potentially actionable genes, that could eventually become drug targets for personalized or individualized therapies, can be easily tested. The PathAct tool can be found at:

Mileo AM, Mattarocci S, Matarrese P, et al.
Hepatitis C virus core protein modulates pRb2/p130 expression in human hepatocellular carcinoma cell lines through promoter methylation.
J Exp Clin Cancer Res. 2015; 34:140 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatitis C Virus (HCV) infection is associated with chronically evolving disease and development of hepatocellular carcinoma (HCC), albeit the mechanism of HCC induction by HCV is still controversial. The nucleocapsid (core) protein of HCV has been shown to be directly implicated in cellular transformation and immortalization, enhancing the effect of oncogenes and decreasing the one of tumor suppressor genes, as RB1 and its protein product pRB. With the aim of identifying novel molecular mechanisms of hepatocyte transformation by HCV, we examined the effect of HCV core protein on the expression of the whole Retinoblastoma (RB) family of tumor and growth suppressor factors, i.e. pRb, p107 and pRb2/p130.
METHODS: We used a model system consisting of the HuH-7, HCV-free, human hepatocellular carcinoma cell line and of the HuH-7-CORE cells derived from the former and constitutively expressing the HCV core protein. We determined pRb, p107 and pRb2/p130 protein and mRNA amount of the respective genes RB1, RBL1 and RBL2, RBL2 promoter activity and methylation as well as DNA methyltransferase 1 (DNMT1) and 3b (DNMT3b) expression level. The effect of pRb2/p130 over-expression on the HCV core-expressing HuH-7-CORE cells was also evaluated.
RESULTS: We found that the HCV core protein expression down-regulated pRb2/p130 protein and mRNA levels in HuH-7-CORE cells by inducing promoter hyper-methylation with the concomitant up-regulation of DNMT1 and DNMT3b expression. When pRb2/p130 expression was artificially re-established in HuH-7-CORE cells, cell cycle analysis outlined an accumulation in the G0/G1 phase, as expected.
CONCLUSIONS: HCV core appears indeed able to significantly down-regulate the expression and the function of two out of three RB family tumor and growth suppressor factors, i.e. pRb and pRb2/p130. The functional consequences at the level of cell cycle regulation, and possibly of more complex cell homeostatic processes, may represent a plausible molecular mechanism involved in liver transformation by HCV.

Meng WJ, Pathak S, Ding ZY, et al.
Special AT-rich sequence binding protein 1 expression correlates with response to preoperative radiotherapy and clinical outcome in rectal cancer.
Cancer Biol Ther. 2015; 16(12):1738-45 [PubMed] Free Access to Full Article Related Publications
Our recent study showed the important role of special AT-rich sequence binding protein 1 (SATB1) in the progression of human rectal cancer. However, the value of SATB1 in response to radiotherapy (RT) for rectal cancer hasn't been reported so far. Here, SATB1 was determined using immunohistochemistry in normal mucosa, biopsy, primary cancer, and lymph node metastasis from 132 rectal cancer patients: 66 with and 66 without preoperative RT before surgery. The effect of SATB1 knockdown on radiosensitivity was assessed by proliferation-based assay and clonogenic assay. The results showed that SATB1 increased from normal mucosa to primary cancer, whereas it decreased from primary cancer to metastasis in non-RT patients. SATB1 decreased in primary cancers after RT. In RT patients, positive SATB1 was independently associated with decreased response to preoperative RT, early time to metastasis, and worse survival. SATB1 negatively correlated with ataxia telangiectasia mutated (ATM) and pRb2/p130, and positively with Ki-67 and Survivin in RT patients, and their potential interaction through different canonical pathways was identified in network ideogram. Taken together, our findings disclose for the first time that radiation decreases SATB1 expression and sensitizes cancer cells to confer clinical benefit of patients, suggesting that SATB1 is predictive of response to preoperative RT and clinical outcome in rectal cancer.

Kim ST, Sohn I, DO IG, et al.
Transcriptome analysis of CD133-positive stem cells and prognostic value of survivin in colorectal cancer.
Cancer Genomics Proteomics. 2014 Sep-Oct; 11(5):259-66 [PubMed] Related Publications
BACKGROUND/AIM: CD133 is an important, but not exclusive, biomarker of colorectal cancer (CRC) stem cells.
MATERIALS AND METHODS: In order to identify other CRC stem cell-specific genes, we performed a comparative expression profiling of CD133(+) and CD133(-) cell populations in primary and metastatic tumors from four patients with CRC. CD133(+) and CD133(-) CRC cells were isolated using MagSweeper and used for whole-transcriptome analysis with RNA-Seq.
RESULTS: We found that in CD133(+) cells, 17 genes (RNASE2, PRB2, IL4, MGC27382, CLEC4C, SALL3, GIMAP1, ISG15, LOC728875, ZIK1, ICAM2, CCDC7, CDYL2, LRRC2, ZEB1, OSTF1 and CCDC144B) were significantly up-regulated compared to CD133(-) CRC cells. Among them, IL4 has been known as an inducer of survivin implicated in the survival and proliferation of cancer cells. However, the prognostic value of survivin in CRC is controversial. We evaluated survivin expression in formalin-fixed paraffin-embedded tumor samples of 188 patients with CRC by immunohistochemistry. Survivin over-expression was detected in 85 patients (45.2%) and was significantly associated with primary tumor sites (p=0.028), lymph node metastasis (p=0.029) and advanced III/IV CRC stages (AJCC 7; p=0.001). Furthermore, survivin up-regulation correlated with reduced disease-free survival (DFS; p=0.021) and overall survival (OS; p<0.000) and was proved to be an independent prognostic factor for both DFS and OS in multivariate analysis.
CONCLUSION: Our data suggest that CD133(+) CRC stem cells have a distinct expression pattern and that survivin, up-regulated by differentially expressed IL-4, is a candidate biomarker for the prediction of recurrence and survival in CRC.

Cito L, Indovina P, Forte IM, et al.
pRb2/p130 localizes to the cytoplasm in diffuse gastric cancer.
J Cell Physiol. 2015; 230(4):802-5 [PubMed] Related Publications
pRb2/p130 is a key tumor suppressor, whose oncosuppressive activity has mainly been attributed to its ability to negatively regulate cell cycle by interacting with the E2F4 and E2F5 transcription factors. Indeed, pRb2/p130 has been found altered in various cancer types in which it functions as a valuable prognostic marker. Here, we analyzed pRb2/p130 expression in gastric cancer tissue samples of diffuse histotype, in comparison with their normal counterparts. We found a cytoplasmic localization of pRb2/p130 in cancer tissue samples, whereas, in normal counterparts, we observed the expected nuclear localization. pRb2/p130 cytoplasmic delocalization can lead to cell cycle deregulation, but considering the emerging involvement of pRb2/p130 in other key cellular processes, it could contribute to gastric tumorigenesis also through other mechanisms. Our data support the necessity of further investigations to verify the possibility of using pRb2/p130 as a biomarker or potential therapeutic target for diffuse gastric cancer.

Suzuki K, Sakaguchi M, Tanaka S, et al.
Prolyl oligopeptidase inhibition-induced growth arrest of human gastric cancer cells.
Biochem Biophys Res Commun. 2014; 443(1):91-6 [PubMed] Related Publications
Prolyl oligopeptidase (POP) is a serine endopeptidase that hydrolyzes post-proline peptide bonds in peptides that are <30 amino acids in length. We recently reported that POP inhibition suppressed the growth of human neuroblastoma cells. The growth suppression was associated with pronounced G0/G1 cell cycle arrest and increased levels of the CDK inhibitor p27(kip1) and the tumor suppressor p53. In this study, we investigated the mechanism of POP inhibition-induced cell growth arrest using a human gastric cancer cell line, KATO III cells, which had a p53 gene deletion. POP specific inhibitors, 3-({4-[2-(E)-styrylphenoxy]butanoyl}-l-4-hydroxyprolyl)-thiazolidine (SUAM-14746) and benzyloxycarbonyl-thioprolyl-thioprolinal, or RNAi-mediated POP knockdown inhibited the growth of KATO III cells irrespective of their p53 status. SUAM-14746-induced growth inhibition was associated with G0/G1 cell cycle phase arrest and increased levels of p27(kip1) in the nuclei and the pRb2/p130 protein expression. Moreover, SUAM-14746-mediated cell cycle arrest of KATO III cells was associated with an increase in the quiescent G0 state, defined by low level staining for the proliferation marker, Ki-67. These results indicate that POP may be a positive regulator of cell cycle progression by regulating the exit from and/or reentry into the cell cycle by KATO III cells.

Kalungi S, Wabinga H, Bostad L
The RB (pRb2/p16) and p53 (p14/p53/p21) tumor-suppressor pathways in endemic Burkitt lymphoma.
J Pediatr Hematol Oncol. 2011; 33(2):e54-9 [PubMed] Related Publications
Burkitt lymphoma accounts for approximately 50% of pediatric cancers in equatorial Africa and a majority of NHL in Uganda. The aim of the study was to examine the expression profile of the RB (pRb2 or p16) and p53 (p53, p14, or p21) pathways in biopsies of endemic BL, and compare it to the pattern found in reactive lymphoid hyperplasia (RLH). A total of 51 BL and 10 RLH biopsy specimens were included in the study. p16 expression was found in 8 (16.3%) BL and 2 (20%) RLH cases. p27 was revealed in 29 (65.9%)BL and 9(90%) RLH cases, whereas 29(59.2%) BL and only 1 RLH expressed p53. Positivity for pRb2 was found in 42 (84.0%) of the BL and 8(80%)of the RLH cases. p21 and p14 were negative in all BL and RLH cases. In conclusion, our data indicate that heterogeneous RB (pRb2 or p16) and p53 (p53, p14, or p21) pathway alterations occur frequently in BL. Except for a much higher frequency of p53 protein expression in BL, close similarities were found between BL and RLH.

Cito L, Pentimalli F, Forte I, et al.
Rb family proteins in gastric cancer (review).
Oncol Rep. 2010; 24(6):1411-8 [PubMed] Related Publications
Gastric cancer is one of the most diffuse neoplastic pathologies in the world whose environmental and molecular causes, although deeply investigated, have not been completely clarified. Besides some well-established etiological factors, such as Helicobacter pylori and E-cadherin mutations, investigations on other possible causes gave contrasting results. Rb family proteins (including pRb/p105, pRb2/p130 and p107) are involved in cell cycle regulation and their function and/or expression is often lost in various kinds of tumours such as lung, bladder, breast and brain cancer. The consequences of RB inactivation in tumours can be very different depending on the context and the type of cancer. Recent evidence indicates that Rb status correlates with a different therapeutic response according to the tumour type and the therapeutic agent. Studies performed on Rb family proteins in gastrointestinal tract tumours suggest that these proteins have an important role in these cancer types. However, owing to contrasting results, further investigation is required to assess whether the expression of Rb family proteins can potentially be used as a prognostic or predictive factor in gastric cancer.

Caracciolo V, Macaluso M, D'Agostino L, et al.
Cross-talk between T-Ag presence and pRb family and p53/p73 signaling in mouse and human medulloblastoma.
J Cell Biochem. 2010; 110(1):182-90 [PubMed] Free Access to Full Article Related Publications
The formation and progression of mudulloblastoma (MB) is poorly understood. However, somatic inactivation of pRb/p105, in combination with a somatic or a germ-line TP53 inactivation, leads to MB in a mouse model. Presently, there is no specific evidence of pathway/s alterations for the other two members of the retinoblastoma family, pRb2/p130 and/or p107 in MB. JC virus (JCV) is a human polyomavirus. Although there is no firm evidence that this virus plays a causal role in human neoplasia, it has been clearly proven that JCV is highly oncogenic when injected into the brain of experimental animals. The mechanism of JCV-induced tumorigenesis is not entirely clear. However, several studies relate the oncogenic properties of JCV mainly to its early protein large T-antigen (T-Ag), which is able to bind and inactivate both TP53 and Rb family proteins. Here, we compared the protein expression profiles of p53, p73, pRb family proteins, and PCNA, as main regulators of cell proliferation and death, in different cell lines of mouse primitive neuroectodermal tumors (PNET), either T-Ag-positive or -negative, and in human MB cell lines. Our goal was to determine if changes in the relative expression of these regulators could trigger molecular perturbations underlying MB pathogenesis in mouse and human cells. Our results support that the presence of JCV T-Ag may interfere with the expression of pRb family proteins, specific p73 isoforms, and p53. In turn, this "perturbation" may trigger a network of signals strictly connected with survival and apoptosis.

Masciullo V, Berardengo E, Boglione A, et al.
The retinoblastoma family member pRb2/p130 is an independent predictor of survival in human soft tissue sarcomas.
Clin Cancer Res. 2008; 14(15):4775-9 [PubMed] Related Publications
PURPOSE: pRb2/p130, a member of the Retinoblastoma gene family, has been shown to be a powerful prognostic factor in several malignancies. We sought to evaluate pRb2/p130 protein expression and its clinical effect in patients affected with soft tissue sarcomas (STS).
EXPERIMENTAL DESIGN: Expression of pRb2/p130 was evaluated by immunohistochemistry on formalin-fixed, paraffin-embedded sections in 41 STSs. Results obtained were correlated with clinicopathologic variables and disease-free and overall survival (OS) in univariate and multivariate analysis.
RESULTS: Expression of pRb2/p130 was diminished in 25 (61%) tumors, whereas the remaining ones (39%) were classified as high expressors. No correlation between pRb2/p130 expression and clinicopathologic variables was observed. However, a direct relationship between pRb2/p130 expression and clinical outcome of the patients was found in the subgroup of nonmetastatic tumors (n = 31). In univariate analysis, reduced pRb2/p130 expression was a negative prognostic factor and correlated with shorter disease-free survival (P = 0.021) and OS (P = 0.017) survival. In multivariate analysis, reduced pRb2/p130 expression was confirmed to be an independent predictor of shorter OS when considered together with tumor stage and grading (risk ratio, 7.893; confidence interval, 1.618-38.509; P = 0.011).
CONCLUSIONS: This study shows for the first time the potential prognostic value of pRb2/130 expression evaluated on formalin-fixed, paraffin-embedded sections in STSs patients. pRb2/p130 immunoreactivity can be used to predict OS in patients with nonmetastatic STSs and, therefore, may represent a new prognostic marker.

Sun A, Bagella L, Tutton S, et al.
From G0 to S phase: a view of the roles played by the retinoblastoma (Rb) family members in the Rb-E2F pathway.
J Cell Biochem. 2007; 102(6):1400-4 [PubMed] Related Publications
Tumor suppressor pRb/p105, pRb/p107, and pRb2/p130 genes belong to the retinoblastoma (Rb) gene family. The members of the Rb gene family and the transcription factor E2F play an essential role in regulating cell cycle and, consequently, cell proliferation. This mini-review describes the mechanisms by which Rb family members and E2F regulate cell cycle progression.

Giordano A, Rossi A, Romano G, Bagella L
Tumor suppressor pRb2/p130 gene and its derived product Spa310 spacer domain as perspective candidates for cancer therapy.
J Cell Physiol. 2007; 213(2):403-6 [PubMed] Related Publications
Tumor suppressor pRb2/p130 gene belongs to the retinoblastoma (Rb) gene family, which also includes pRb/p105 and pRb/p107. The members of the Rb gene family have attracted a great deal of interest because of their essential role in regulating cell cycle and, consequently, cell proliferation. This mini review discusses the potential therapeutic applications both of pRb2/p130 and its derived product Spa310 spacer domain in cancer treatment.

Macaluso M, Montanari M, Noto PB, et al.
Epigenetic modulation of estrogen receptor-alpha by pRb family proteins: a novel mechanism in breast cancer.
Cancer Res. 2007; 67(16):7731-7 [PubMed] Related Publications
Estrogen receptor-alpha (ER-alpha) plays a crucial role in normal breast development and has also been linked to mammary carcinogenesis and clinical outcome in breast cancer patients. However, ER-alpha gene expression can change during the course of disease and, consequently, therapy resistance can occur. The molecular mechanism governing ER-alpha transcriptional activity and/or silencing is still unclear. Here, we showed that the presence of a specific pRb2/p130 multimolecular complex on the ER-alpha promoter strongly correlates with the methylation status of this gene. Furthermore, we suggested that pRb2/p130 could cooperate with ICBP90 (inverted CCAAT box binding protein of 90 kDa) and DNA methyltransferases in maintaining a specific methylation pattern of ER-alpha gene. The sequence of epigenetic events for establishing and maintaining the silenced state of ER-alpha gene can be locus- or pathway- specific, and the local remodeling of ER-alpha chromatin structure by pRb2/p130 multimolecular complexes may influence its susceptibility to specific DNA methylation. Our novel hypothesis could provide a basis for understanding how the complex pattern of ER-alpha methylation and transcriptional silencing is generated and for understanding the relationship between this pattern and its function during the neoplastic process.

Vinodhkumar R, Song YS, Devaki T
Romidepsin (depsipeptide) induced cell cycle arrest, apoptosis and histone hyperacetylation in lung carcinoma cells (A549) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression.
Biomed Pharmacother. 2008; 62(2):85-93 [PubMed] Related Publications
Histone deacetylase inhibitor such as romidepsin (depsipeptide, FR901228, FK228) is a promising new class of antineoplastic agent with the capacity to induce growth arrest and/or apoptosis of cancer cells. However, their precise mechanism of action is uncertain. Histone acetylation and deacetylation are involved in transcriptional activation and transcriptional repression, respectively. Romidepsin induced histone hyperacetylation can be correlated with the cell cycle arrest and apoptosis. In the present study, we investigated the effects of romidepsin on cell proliferation, cell cycle arrest, apoptosis and histone hyperacetylation. Expression of Cdc2/Cdk-1, cyclin B1, cyclin A, p21/Cip1, pRb, pRb2/p130, histone H4 and H3 acetylation status were studied with western blot analysis. The induction of apoptosis has been demonstrated by annexin V-FITC binding assay. Extent of apoptosis has been assessed measuring the activity of caspase-3. Romidepsin led to substantial decrease in the expression of Cdc2/Cdk-1, cyclin B1 and phosphorylated pRb and increase in p21. The pRb protein was found to be one of the targets for the romidepsin induced cell cycle arrest. Flow cytometric analysis showed that romidepsin induced cell cycle arrest at G2-M transition, with significant induction of apoptosis at 25 and 50 nM concentration of romidepsin, with an increase in the number of both early and late apoptotic cells. From this study it is concluded that romidepsin inhibit advanced human lung carcinoma (A549) cell proliferation by altering the expression of cell cycle regulators and apoptotic protein.

Caracciolo V, Reiss K, Crozier-Fitzgerald C, et al.
Interplay between the retinoblastoma related pRb2/p130 and E2F-4 and -5 in relation to JCV-TAg.
J Cell Physiol. 2007; 212(1):96-104 [PubMed] Related Publications
Human polyomaviruses, which include JC virus (JCV) and BK virus (BKV), as well as the simian virus 40 (SV40), have been associated with human tumors and have been shown to be highly tumorigenic in experimental animal models. Although the mechanism by which JCV induces tumorigenesis is not entirely clear, earlier studies point to the involvement of the viral early protein T-antigen which has the ability to bind and inactivate tumor suppressors and cell cycle regulatory proteins, such as the retinoblastoma family proteins and p53. We investigated if the distribution between nucleus and cytoplasm of the transcription factors E2F4 and E2F5 is mediated by pRb2/p130 and if the presence of JCV T-antigen may impair this shuttling by sequestering pRb2/p130. The results showed that E2F4 was prevalently localized in the nucleus of both T-antigen positive and -negative R503 cells independently of the cell cycle phase. E2F5 instead was prevalently localized in the cytoplasmic fraction in G(0)/G(1), S-phase synchronized, and asynchronous R503 and R503 T-Ag positive cells. The presence of T-antigen did not influence the subcellular localization of these transcription factors E2F4 and E2F5, at least in this murine cellular model. Moreover, Small interference RNA experiments directed toward silencing the Rb2/p130 gene demonstrated that pRb2/p130 does not play a predominant role in the nuclear transportation of E2F4 and E2F5.

Mattioli E, Vogiatzi P, Sun A, et al.
Immunohistochemical analysis of pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expression patterns in gastric cancer.
J Cell Physiol. 2007; 210(1):183-91 [PubMed] Related Publications
Although the considerable progress against gastric cancer, it remains a complex lethal disease defined by peculiar histological and molecular features. The purpose of the present study was to investigate pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expressions, and analyze their possible correlations with clinicopathological factors. The expression patterns were examined by immunohistochemistry in 47 patients, 27 evaluated of intestinal-type, and 20 of diffuse-type, with a mean follow up of 56 months and by Western blot in AGS, N87, KATO-III, and YCC-2, -3, -16 gastric cell lines. Overall, stomach cancer showed EZH2 correlated with high levels of p53, Ki-67, and cytoplasmic pRb2/p130 (P < 0.05, and P < 0.01, respectively). Increased expression of EZH2 was found in the intestinal-type and correlated with the risk of distant metastasis (P < 0.05 and P < 0.01, respectively), demonstrating that this protein may have a prognostic value in this type of cancer. Interestingly, a strong inverse correlation was observed between p27(KIP1) expression levels and the risk of advanced disease and metastasis (P < 0.05), and a positive correlation between the expression levels of p21(WAF1) and low-grade (G1) gastric tumors (P < 0.05), confirming the traditionally accepted role for these tumor-suppressor genes in gastric cancer. Finally, a direct correlation was found between the expression levels of nuclear pRb2/p130 and low-grade (G1) gastric tumors that was statistically significant (P < 0.05). Altogether, these data may help shed some additional light on the pathogenetic mechanisms related to the two main gastric cancer histotypes and their invasive potentials.

De Falco G, Giordano A
pRb2/p130: a new candidate for retinoblastoma tumor formation.
Oncogene. 2006; 25(38):5333-40 [PubMed] Related Publications
Retinoblastoma is the most common primary intraocular tumor in childhood. Mutations in both the alleles of the RB1 gene represent the causative agent for the tumor to occur. It is becoming evident that, although these alterations represent key events in the genesis of retinoblastoma, they are not sufficient per se for the tumor to develop, and other additional genetic or epigenetic alterations must occur. A supportive role in the genesis of retinoblastoma has recently been proposed for the RB1-related gene RB2/p130. Additionally, several other genetic alterations involving different chromosomes have been described as relevant in the tumorigenic process. In this review we will analyse current knowledge about the molecular mechanisms involved in retinoblastoma, paying particular attention to the mechanisms of inactivation of the biological function of the retinoblastoma family of proteins.

Gabellini C, Del Bufalo D, Zupi G
Involvement of RB gene family in tumor angiogenesis.
Oncogene. 2006; 25(38):5326-32 [PubMed] Related Publications
Angiogenesis, the development of new blood vessels from pre-existing vessels, represents a fundamental step in tumor progression and metastatization. The induction of vasculature is required for growth of the tumor mass, to ensure an adequate supply of oxygen and metabolites to the tumor beyond a critical size. Tumor angiogenesis is a highly regulated process that is controlled physiologically by the tumor microenvironment and genetically by alteration of several oncogenes or tumor suppressor genes. We will focus on recent demonstrations regarding the involvement of the retinoblastoma family proteins (phosphorylated retinoblastoma (pRb), p107 and pRb2/p130) at different levels of the angiogenic process. pRb and its homologs can regulate the expression of pro- and antiangiogenic factors, such as the vascular endothelial growth factor, through an E2F-dependent mechanism. Moreover, pRb is able to modulate also the transcriptional activity of several angiogenesis-related factors like HIF-1, Id2 and Oct-1. pRb2/p130 is required for both differentiation and mobilization of bone marrow-derived endothelial cell precursors and endothelial sprouting from neighboring vessels. The involvement of the pRb pathway in the angiogenesis process has also been demonstrated by different cellular models expressing viral oncoproteins, like human papilloma virus. Moreover, some natural and synthetic compounds demonstrate their antiangiogenetic activity with a mechanism of action involving pRb. Finally, the possible prognostic value of immunohistochemical evaluation of pRb and/or pRb2/p130 expression can represent a useful tool for the characterization of the angiogenic phenotype of specific tumor histotypes.

Leoncini L, Bellan C, De Falco G
Retinoblastoma gene family expression in lymphoid tissues.
Oncogene. 2006; 25(38):5309-14 [PubMed] Related Publications
It appears more and more clear that retinoblastoma (RB) family of proteins represents key molecules in tumour suppression. This family consists of pRb/p105, p107 and pRb2/p130, which participate in a gene regulatory network that governs the cellular response to antimitogenic signals, and whose deregulation constitutes one of the hallmarks of cancer. Irrespective of their structural and biochemical similarities, RB proteins carry out different functional tasks. The expression of RB gene family in the reactive lymphoid tissues again confirms the different role of each member in cell cycle control and differentiation of normal cells. These different functional properties appear to be maintained in tumours lymphoid tissues, where alterations of the RB/p105 gene appear to be relatively rare. In this review, we will summarize the current knowledge about the role of the RB proteins in reactive and neoplastic lymphoid tissue.

Scambia G, Lovergine S, Masciullo V
RB family members as predictive and prognostic factors in human cancer.
Oncogene. 2006; 25(38):5302-8 [PubMed] Related Publications
The retinoblastoma family members--pRb, pRb2/p130 and p107--are tumor suppressor genes involved in controlling four major cellular processes: growth arrest, apoptosis, differentiation and angiogenesis. Molecular genetic studies have identified abnormalities of these tumor suppressor genes in a large proportion of human cancers. These genetic alterations have emerged as significant factors in the pathogenesis and progression of many types of tumors and are therefore likely to provide relevant information to assess risk in cancer patients. There is a pressing clinical need to identify prognostic and predictive factors for patients with cancer, because there is an undeniable importance in being able to determine which patients will have a favorable outcome without further therapy (prognostic factor) and which will need some additional treatment (predictive factor). This review examines the predictive and/or prognostic role of each retinoblastoma family member in human cancer.

Caracciolo V, Reiss K, Khalili K, et al.
Role of the interaction between large T antigen and Rb family members in the oncogenicity of JC virus.
Oncogene. 2006; 25(38):5294-301 [PubMed] Related Publications
Human polyomaviruses (JC virus, BK virus and simian virus 40) are causative agents of some human diseases and, interestingly, are involved in processes of cell transformation and oncogenesis. These viruses need the cell cycle machinery of the host cell to complete their replication; so they evolved mechanisms that can interfere with the growth control of infected cells and force them into DNA replication. The retinoblastoma family of proteins (pRb), which includes pRb/p105, p107 and pRb2/p130, acts as one of the most important regulators of the G1/S transition of the cell cycle. Rb proteins represent an important target for viral oncoproteins. Early viral T antigens can bind all members of the pRb family, promoting the activation of the E2F family of transcription factors, thus inducing the expression of genes required for the entry to the S phase. The interaction between early viral antigens and cell cycle regulators represents an important mechanism through which viruses deregulate cell cycle and lead to cell transformation. In this review, we will discuss the effects of the interaction between large T antigen and Rb proteins in JC virus-mediated oncogenesis.

Genovese C, Trani D, Caputi M, Claudio PP
Cell cycle control and beyond: emerging roles for the retinoblastoma gene family.
Oncogene. 2006; 25(38):5201-9 [PubMed] Related Publications
Rb family proteins (pRb/p105, Rb2/p130 and p107) play a key role in cell cycle control and are worthily involved in transcription repression and tumor suppression. The mechanisms of transcriptional activation and repression by the Rb gene family has been extensively investigated: pRb, pRb2/p130 and p107 interact with different E2F family factors and can inhibit E2F responsive promoters, interfering with progression of cell cycle, gene transcription, initiation of apoptotic process and cell differentiation. Recent studies have indicated that Rb and Rb2/p130 may be involved in cellular response to DNA damage events, by influencing the transcription of factors involved in DNA repair pathways. In particular, evidences suggest that Rb loss and target gene deregulation impacts on the repair of UV-induced pyrimidine pyrimidone photoproducts (6-4 PP) by regulating the expression of several DNA damage factors involved in UV DNA damage repair processes, including proliferating cell nuclear antigen. Ongoing studies are focused on the mechanisms by which Rb family genes drive cell cycle exit following DNA damage induction, and how Rb gene family's interaction with chromatin remodeling factors can influence DNA repair dynamics.

Macaluso M, Montanari M, Noto PB, et al.
Nuclear and cytoplasmic interaction of pRb2/p130 and ER-beta in MCF-7 breast cancer cells.
Ann Oncol. 2006; 17 Suppl 7:vii27-9 [PubMed] Related Publications
Estrogens exhibit important biological functions and influence several pathological processes of hormone-dependent diseases. The biological actions of estrogens require their interaction with two estrogen receptors (ER-alpha and ER-beta), which are ligand-dependent transcription factors. ER-alpha and ER-beta exhibit distinct tissue expression patterns as well as show different patterns of gene regulation. In addition, it has been suggested that ER-beta works as a counter partner of ER-alpha through inhibition of the transactivating functions of ER-alpha. For instance, ER-beta seems to play a different role in breast tumorigenesis than ER-alpha, as ER-beta decreased expression in breast cancer has been correlated with bad prognosis. Biological activities of ER-alpha and ER-beta could be controlled by a number of interacting proteins such as activators/inhibitors, ligand binding and kinases. We have previously reported that pRb2/p130, retinoblastoma related protein, could be involved in the silencing of ER-alpha gene during breast tumorigenesis. Here, we report that ER-beta and pRb2/p130 proteins co-immunoprecipitate in both nucleus and cytoplasm of MCF-7 breast cancer cells. Our hypothesis is that the interaction of pRb2/130 with ER-beta may have a functional significance in regulating ER-beta activity.

Bergqvist M, Brattström D, Brodin D, et al.
Genes associated with telomerase activity levels in esophageal carcinoma cell lines.
Dis Esophagus. 2006; 19(1):20-3 [PubMed] Related Publications
Telomerase activity levels have been shown to correlate with tumor progression in several malignancies. However, the genetic regulation of telomerase activity levels is not fully understood. The aim of the present study has been to identify a gene expression profile, predicting correlation with the telomerase-activity test. Ten human esophageal carcinoma cell lines were investigated using the telomerase activity assay (TRAPeze) Telomerase Detection Kit), followed by further characterization using the GeneChip Human Genome U133A 2.0 Array (Affymetrics Inc., USA), including 14 500 human genes. Telomerase activity levels were detected in all cell lines with a broad range of activity levels. Using a high correlation coefficient, r > 0.90, the following genes were found to be positively correlated with telomerase activity levels: N-myristoyltransferase 2; ribosomal protein L3; retinoblastoma-like 2 (pRb2/p130); and cyclin G2. Only one gene was negatively correlated with telomerase activity levels, zinc finger protein 207. In conclusion, the present microarray data provide primary validation data indicating possible candidates for prognostic and prediction factors in esophageal cancer in relation to telomerase activity.

Sanseverino F, Santopietro R, Torricelli M, et al.
pRb2/p130 and VEGF expression in endometrial carcinoma in relation to angiogenesis and histopathologic tumor grade.
Cancer Biol Ther. 2006; 5(1):84-8 [PubMed] Related Publications
PURPOSE: Endometrial cancer is the most common gynecologic malignancy. Established prognostic factors are histologic grade, depth of myometrial invasion, and extrauterine spread including retroperitoneal lymph node metastases. Tumorigenesis is a multistep process involving different genetic changes resulting in uncontrolled cellular proliferation, inhibition of apoptosis, and enhanced vascular proliferation among other events. Angiogenesis, the formation of new blood vessels from a preexisting vascular network, is necessary for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. The pathogenesis of the angiogenetic phenotype may involve the inactivation of different tumor suppressor genes.
EXPERIMENTAL DESIGN: We investigated the relationship between the expression levels of VEGF and the retinoblastoma family member pRb2/p130 in endometrial carcinoma in relation to histopathologic tumor grade in a cohort of 50 patients.
RESULTS: We found that VEGF and pRB2/p130 expression were inversely correlated. Additionally, high grade tumors presented a significantly lower number of cells expressing pRb2/p130 when compared to low grade tumors. A significant positive correlation was found, by means of the Spearman coefficient, between VEGF expression and binary grading (0.450, p-value < 0.005) which is an architectural grading system that uses low-magnification assessment of amount of solid growth, pattern of invasion, and presence of necrosis to divide endometrioid carcinomas into low- and high-grade tumors. Additionally, we also found a negative correlation between pRb2/p130 expression levels and binary grading (-0.595, p-value < 0.005). Interestingly, we also found that VEGF and pRb2/p130 expression levels were not related to staging (p-value > 0.005).
CONCLUSIONS: These results open up a new perspective including novel markers that, combined together, may be useful in patient screening for endometrial cancer aggressiveness.

Vijayababu MR, Kanagaraj P, Arunkumar A, et al.
Quercetin-induced growth inhibition and cell death in prostatic carcinoma cells (PC-3) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression.
J Cancer Res Clin Oncol. 2005; 131(11):765-71 [PubMed] Related Publications
Prostate cancer is the major health problem and the leading cause of male cancer death. Quercetin is a novel antitumor and antioxidant, whose molecular mechanism involved in cell cycle arrest in androgen independent prostate cancer cells remains unclear. In this study, we investigated the effects of quercetin on proliferation and cell cycle arrest by modulation of Cdc2/Cdk-1 protein in prostate cancer cells (PC-3). PC- 3 cells are human androgen independent cancer cells and were cultured with quercetin at concentrations of 50 and 100 microM for 24 h. Cell proliferation, apoptosis and cell cycle distribution were analyzed. Expression of Cdc2/Cdk-1, cyclin B1, cyclin A, p21/Cip1, pRb, pRb2/p130, Bcl-2, Bcl-X(L), Bax and caspase-3 proteins were studied with western blot analysis. Addition of quercetin led to substantial decrease in the expression of Cdc2/Cdk-1, cyclin B1 and phosphorylated pRb and increase in p21. Flowcytometric analysis showed that quercetin blocks G2-M transition, with significant induction of apoptosis. Apoptosis markers like Bcl-2 and Bcl-X(L) were significantly decreased and Bax and caspase-3 were increased. From this study, it was concluded that quercetin inhibits prostate cancer cell proliferation by altering the expression of cell cycle regulators and apoptotic proteins.

Cinti C, Macaluso M, Giordano A
Tumor-specific exon 1 mutations could be the 'hit event' predisposing Rb2/p130 gene to epigenetic silencing in lung cancer.
Oncogene. 2005; 24(38):5821-6 [PubMed] Related Publications
Genetic alterations in Rb2/p130 gene have been reported in several tumors, but till now there are insufficient and conflicting data linking the loss of pRb2/p130 expression with the mutational status of this gene in lung cancer. We recently reported that loss or lowering of pRb2/p130 expression is mainly due to aberrant Rb2/p130 promoter methylation, in retinoblastoma tumors, and indicated that epigenetic silencing of Rb2/p130 can impair its function to negatively regulate cell cycle progression as well as apoptotic response. In order to clarify Rb2/p130 gene inactivation in lung cancer, we investigated whether epigenetic events could impair the expression of this gene in NSLC. Here, we show that specific Rb2-exon 1 homozygous mutations, occurring in an Rb2/p130, region, rich in CpG dinucleotides, could be the 'hit event' that predispose this gene to epigenetic changes, leading to Rb2/p130 gene silencing in lung cancer. Moreover, these homozygous mutations, found in different tumor histotypes, could represent tumor-specific markers.

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