ym.edu.tw.Abstract. Amyloid beta-peptide (Aβ), the neurotoxic component of senile plaques in Alzheimers disease (AD) brains, is known to trigger cell cycle reentry in post-mitotic neurons followed by apoptosis. However, the underlying mechanisms remain unclear. Recently, we have reported that Aβs stimulate the expression of inhibitor of differentiation-1 (Id1) to induce sonic hedgehog (SHH) (Hung et al., Mol Neurobiol 53(2):793-809, 2016), and both are mitogens capable of triggering cell cycle progression. In this work, we tested the hypothesis that Aβ-induced Id1 and SHH contribute to cell cycle reentry leading to apoptosis in neurons. We found that Aβ triggered cell cycle progression in the post-mitotic neurons, as indicated by the increased expression of two G1-phase markers including cyclin D1 and phosphorylated retinoblastoma protein (pRb), two G2-phase markers such as proliferating cell nuclear antigen (PCNA) and incorporation of 5-bromo-2′-deoxyuridine (BrdU) into newly synthesized ...
TY - JOUR. T1 - SU9516, a cyclin-dependent kinase 2 inhibitor, promotes accumulation of high molecular weight E2F complexes in human colon carcinoma cells. AU - Yu, Bo. AU - Lane, Maureen E.. AU - Wadler, Scott. PY - 2002/10/1. Y1 - 2002/10/1. N2 - The E2F family plays a critical role in the expression of genes required for entry into and progression through S phase. E2F-mediated transcription is repressed by the tumor suppressor retinoblastoma protein (pRb), which results in sequestration of E2F in a multiprotein complex that includes pRb. Derepression of E2F results from a series of complex phosphorylation events mediated by cyclin D/cdk4 and cyclin E/cdk2. We have employed a novel 3-substituted indolinone compound, 3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516), which selectively inhibits cdk2 activity (Lane et al., Cancer Res 2001;61:6170-7) to investigate these events. Electrophoretic mobility gel shift assays were performed on SU9516-treated and ...
TY - JOUR. T1 - Retinoblastoma protein regulates cell proliferation, differentiation, and endoreduplication in plants. AU - Park, Jong A.. AU - Ahn, Joon Woo. AU - Kim, Yu Kyung. AU - Su, Jung Kim. AU - Kim, Ju Kon. AU - Woo, Taek Kim. AU - Pai, Hyun Sook. PY - 2005/4/1. Y1 - 2005/4/1. N2 - Retinoblastoma protein (Rb) plays a key role in cell cycle control, cell differentiation, and apoptosis in animals. In this study, we used virus-induced gene silencing (VIGS) to investigate the cellular functions of Rb in higher plants. VIGS of NbRBR1, which encodes the Nicotiana benthamiana Rb homolog, resulted in growth retardation and abnormal organ development. At the cellular level, Rb suppression caused prolonged cell proliferation in tissues that are normally differentiated, which indicates that Rb is a negative regulator of plant cell division. Furthermore, differentiation of the epidermal pavement cells and trichomes was partially retarded, and stomatal clusters formed in the epidermis, likely due to ...
a) pRB was induced by tetracycline in a stably transfected SAOS2 cell line (SAOS-tetRB) and protein samples for immunoblotting were harvested at various times after pRB induction. GAPDH, loading control. Uncropped images of the gels are shown in the Supplementary Information, Fig. S6e. (b) pRB-mediated G1 arrest of corresponding samples was monitored by FACS counting BrdU-incorporating S-phase cells after tetracycline treatment of parental SAOS2 cells that do not carry inducible pRB (parental, grey bars), and of pRB-inducible SAOS2 as in a (tet-pRB). (c) pRB-APCcdh1 association was monitored over time by immunoprecipitation using anti-pRB antibodies. The pRB antibody concentration was limiting with regard to extract to obtain equal quantities of immunoprecipitated pRB at the different times. Ig: heavy chain. Uncropped images of the gels are shown in the Supplementary Information, Fig. S6f. (d, e) As controls for the specificity of APCcdh1- and pRB-mediated Skp2 protein turnover, SAOS-tetRB cells ...
TY - JOUR. T1 - Racing to block tumorigenesis after pRb loss. T2 - An innocuous point mutation wins with synthetic lethality. AU - Bauzon, Frederick. AU - Zhu, Liang. N1 - Funding Information: We thank members of our laboratory for helpful discussions. This work was supported by grant RO1CA131421 from the NIH-NCI. L.Z. is a recipient of the Irma T. Hirschl Career Scientist Award.. PY - 2010/6/1. Y1 - 2010/6/1. N2 - A major goal of tumor suppressor research is to neutralize the tumorigenic effects of their loss. Since loss of pRb does not induce tumorigenesis in many types of cells, natural mechanisms may neutralize the tumorigenic effects of prb loss in these cells. For susceptible cells, neutralizing the tumorigenic effects of pRb loss could logically be achieved by correcting the deregulated activities of pRb targets to render pRb-deficient cells less abnormal. This line of research has unexpectedly revealed that knocking out the prb target Skp2 did not render Rb1 deficient cells less abnormal ...
Treatment of the WEHI-2131 or CH31 B cell lymphomas with anti-mu or transforming growth factor (TGF)-beta leads to growth inhibition and subsequent cell death via apoptosis. Since anti-mu stimulates a transient increase in c-myc and c-fos transcription in these lymphomas, we examined the role of these proteins in growth regulation using antisense oligonucleotides. Herein, we demonstrate that antisense oligonucleotides for c-myc prevent both anti-mu- and TGF-beta-mediated growth inhibition in the CH31 and WEHI-231 B cell lymphomas, whereas antisense c-fos has no effect. Furthermore, antisense c-myc promotes the appearance of phosphorylated retinoblastoma protein in the presence of anti-mu and prevents the progression to apoptosis as measured by propidium iodide staining. Northern and Western analyses show that c-myc message and the levels of multiple myc proteins were maintained in the presence of antisense c-myc, results indicating that myc species are critical for the continuation of ...
Progress through the G1phase of the mammalian cell cycle is regulated by the ordered synthesis, assembly, and activation of distinct cyclin-CDK holoenzymes (45, 46). Cyclins D1, D2, and D3 are up-regulated as cells exit from quiescence and associate with their major kinase partners CDK4 and CDK6 (3, 29, 32, 53). These two kinase molecules are highly homologous and associate exclusively with the D-type cyclins (3). Numerous studies have implicated cyclin D-CDK4-CDK6 complexes as key regulators of the cell cycle up to a hypothetical point during late G1 (24, 25), the restriction point, when hyperphosphorylation and inactivation of the retinoblastoma tumor suppressor gene product, pRB, occur (37, 44).. In contrast to mitotic cyclin-CDK complexes, the D-type cyclins do not automatically assemble into complexes with either CDK4 or CDK6. For example, when overexpressed in NIH 3T3 cells in the absence of serum, D-type cyclins and CDK4 do not interact efficiently (30). Hence, assembly of D-type cyclins ...
The transcription factor DRTF1/E2F is implicated in the control of cellular proliferation due to its interaction with key regulators of cell cycle progression, such as the retinoblastoma tumour suppressor gene product and related pocket proteins, cyclins and cyclin-dependent kinases. DRTF1/E2F DNA binding activity arises when a member of two distinct ... read more families of proteins, DP and E2F, interact as DP/E2F heterodimers. Here, we report the isolation and characterisation of a new member of the E2F family of proteins, called E2F-5. E2F-5 was isolated through a yeast two hybrid assay in which a 14.5 d.p.c. mouse embryo library was screened for molecules capable of binding to murine DP-1, but also interacts with all known members of the DP family of proteins. E2F-5 exists as a physiological heterodimer with DP-1 in the generic DRTF1/E2F DNA binding activity present in mammalian cell extracts, an interaction which results in co-operative DNA binding activity and transcriptional activation ...
Fingerprint Dive into the research topics of Activation of the retinoblastoma tumor suppressor mediates cell cycle inhibition and cell death in specific cervical cancer cell lines. Together they form a unique fingerprint. ...
HDAC1/2 deficiency leads to a loss of expression of the key transcription factor, a protein called Sox2, which in turn leads to a block in airway epithelial cell development. This is affected in part by deactivating a repressor of expression (derepressing) of two other proteins, Bmp4 and the tumor suppressor Rb1 - targets of HDAC1/2.. In the adult lung, loss of HDAC1/2 leads primarily to increased expression of inhibitors of cell proliferation including the proteins Rb1, p16, and p21. This results in decreased epithelial proliferation in lung injury and inhibition of regeneration. Together, these data support a critical role for HDAC-mediated mechanisms in regulating both development and regeneration of lung tissue. Since HDAC inhibitors and activators are currently in clinical trials for other diseases, including cancer, such compounds could be tested in the future for efficacy in COPD, acute lung injury, and other lung diseases that involve defective repair and regeneration, says Morrisey. ...
p53 and the Retinoblastoma protein (pRb) are two oncosuppressive proteins whose loss of function is linked to the development of many cancers. Both of them play a central role in the regulation of both cell cycle and apoptosis. Different observations have led to a paradigm in which p53 and pRb can regulate each other, pRb playing an important role in the outcome-growth arrest versus apoptosis-of p53 activation.
Arabidopsis; Retinoblastoma; RBR; ABI3; Polycomb; PRC2; Cell fate; Cell cycle; Differentiation; Seedling establishment; Embryo development; Tumor; ...
Seedling establishment is a crucial phase during plant development when the germinating heterotrophic embryo switches to autotrophic growth and dev...
Cell cycle checkpoints are biochemical signal transduction pathways that prevent downstream events from being initiated until upstream processes are completed. We analyzed whether the p53 or pRb tumor suppressors are involved in a checkpoint(s) that prevents DNA rereplication in the presence of drugs that interfere with spindle assembly. Normal mouse and human fibroblasts arrested with a 4N DNA content when treated with nocodazole and Colcemid, whereas isogeneic p53-deficient or pRb-deficient derivatives became polyploid. Flow cytometric and cytogenetic analyses demonstrated that the polyploidy resulted from genomewide rereplication without an intervening mitosis. Thus, p53 and pRb help maintain normal cell ploidy by preventing DNA rereplication prior to mitotic division.. ...
This gene encodes a member of a small family of transcription factors that function through binding of DP interaction partner proteins. The encoded protein recognizes a specific sequence motif in DNA and interacts directly with the retinoblastoma protein (pRB) to regulate the expression of genes involved in the cell cycle. Altered copy number and activity of this gene have been observed in a number of human cancers. There are pseudogenes for this gene on chromosomes 2 and 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013 ...
2604 We demonstrate that Smad3, a key mediator of TGF-beta antiproliferative responses, is a major physiological substrate of G1 cyclin-dependent kinases CDK4 and CDK2. Except for the retinoblastoma protein (Rb) family, Smad3 is the only substrate demonstrated so far for CDK4, and Smad3 can be phosphorylated by CDK4 to a greater extent than Rb. We have mapped both the in vivo and the in vitro CDK4 and CDK2 phosphorylation sites in Smad3. These sites are phosphorylated by CDK4 and CDK2 in vitro and in a cell-cycle dependent manner in vivo. Moreover, we show that their phosphorylation is reduced in CDK4 knockout mouse embryonic fibroblasts (MEF), and their phosphorylation is increased in CDK4 R24C/R24C MEF, which have elevated CDK4 activity. In addition, RNAi experiments also indicate that CDK4 and CDK2 phosphorylate these sites. CDK phosphorylation of Smad3 inhibits its basal as well as TGF-beta induced transcriptional activity, thus preventing activation of the expression of CDK inhibitors p15 ...
Here, we focus on epigenetic changes in leukaemia and MM (multiple myeloma) cells. We show how the histone signature, DNA methylation and levels of select tumour-suppressor proteins can be affected by inhibitors of HDACs (histone deacetylases) and Dnmts (DNA methyltransferases). Both inhibitors, TSA (trichostatin A) and 5-AZA (5-azacytidine), have the ability to change the histone signature in a tumour-specific manner. In MM cells, we observed changes in H3K4 methylation, while in leukaemia cells, H3K9 methylation was especially affected by select inhibitors. Compared with normal peripheral blood lymphocytes, tumour cell samples were characterized by increased H3K9 acetylation, increased H3K4me2, H3K9me2 and HP1 alpha (heterochromatin protein 1 alpha) levels and specific changes were also observed for DNA methylation. Additionally, we showed that the tumour suppressor pRb1 (retinoblastoma protein) is more sensitive to epigenetic-based anti-cancer stimuli than p53. We have found significant ...
TY - JOUR. T1 - pRb2/p130 and p107 control cell growth by multiple strategies and in association with different compartments within the nucleus. AU - Zini, Nicoletta. AU - Trimarchi, Carmela. AU - Claudio, Pier Paolo. AU - Stiegler, Peter. AU - Marinelli, Fiorenzo. AU - Maltarello, Maria Cristina. AU - La Sala, Dario. AU - De Falco, Giulia. AU - Russo, Giuseppe. AU - Ammirati, Giuseppe. AU - Maraldi, Nadir Mario. AU - Giordano, Antonio. AU - Cinti, Caterina. PY - 2001. Y1 - 2001. N2 - It has been recently reported that retinoblastoma family proteins suppress cell growth by regulating not only E2F-dependent mRNA transcription but also rRNA and tRNA transcription and, through HDAC1 recruitment, chromatin packaging. In the present study we report data showing that these various control strategies are correlated, at least in part, with nuclear compartmentalization of retinoblastoma proteins. In a first series of experiments, we showed that pRb2/p130 and p107 are not evenly distributed within the ...
Cooperative activation of tissue-specific genes by pRB and E2F1.: The retinoblastoma tumor suppressor protein pRB is conventionally regarded as an inhibitor of
High-risk human papillomaviruses are causative agents of cervical cancer. Viral protein E7 is required to establish and maintain the pro-oncogenic phenotype in infected cells, but the molecular mechanisms by which E7 promotes carcinogenesis are only partially understood. Our transcriptome analyses in primary human fibroblasts transduced with the viral protein revealed that E7 activates a group of mitotic genes via the activator B-Myb-MuvB complex. We show that E7 interacts with the B-Myb, FoxM1 and LIN9 components of this activator complex, leading to cooperative transcriptional activation of mitotic genes in primary cells and E7 recruitment to the corresponding promoters. E7 interaction with LIN9 and FoxM1 depended on the LXCXE motif, which is also required for pocket protein interaction and degradation. Using E7 mutants for the degradation of pocket proteins but intact for the LXCXE motif, we demonstrate that E7 functional interaction with the B-Myb-MuvB complex and pocket protein degradation ...
The Rb1 gene was the first bona fide tumor suppressor identified and cloned more than 25 years ago. Since then, a plethora of studies have revealed the functions of pRb and the existence of a sophisticated and strictly regulated pathway that modulates such functional roles. An emerging paradox affecting Rb1 in cancer connects the relatively low number of mutations affecting Rb1 gene in specific human tumors, compared with the widely functional inactivation of pRb in most, if not in all, human cancers. The existence of a retinoblastoma family of proteins pRb, p107, and p130 and their potential unique and overlapping functions as master regulators of cell cycle progression and transcriptional modulation by similar processes, may provide potential clues to explain such conundrum. Here, we will review the development of different genetically engineered mouse models, in particular those affecting stratified epithelia, and how they have offered new avenues to understand the roles of the Rb family members and
Binds double-stranded DNA. Binds preferentially to supercoiled DNA and cruciform DNA structures. Seems to be involved in transcriptional regulation. May function as a transcriptional repressor. Could have a role in the regulation of hematopoietic differentiation through activation of unknown target genes. Controls cellular proliferation by modulating the functions of cell cycle regulatory factors including p53/TP53 and the retinoblastoma protein. May be involved in TP53-mediated transcriptional activation by enhancing TP53 sequence-specific DNA binding and modulating TP53 phosphorylation status. Seems to be involved in energy-level-dependent activation of the ATM/ AMPK/TP53 pathway coupled to regulation of autophagy. May be involved in regulation of TP53-mediated cell death also involving BRCA1. May be involved in the senescence of prostate epithelial cells. Involved in innate immune response by recognizing viral dsDNA in the cytosol and probably in the nucleus. After binding to viral DNA in the ...
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TY - JOUR. T1 - Clinical stratification of glioblastoma based on alterations in retinoblastoma tumor suppressor protein (RB1) and association with the proneural subtype. AU - Goldhoff, Patricia. AU - Clarke, Jennifer. AU - Smirnov, Ivan. AU - Berger, Mitchel S.. AU - Prados, Michael D.. AU - James, C. David. AU - Perry, Arie. AU - Phillips, Joanna J.. N1 - Copyright: Copyright 2012 Elsevier B.V., All rights reserved.. PY - 2012/1. Y1 - 2012/1. N2 - A recent study of CDK4/6 inhibitors in glioblastoma (GBM) xenografts identified retinoblastoma tumor suppressor protein RB1 status as a determinant of tumor therapeutic efficacy. Because of the need for clinically applicable RB1 testing, we assessed the utility of 2 complementary methods for determining RB1 status in GBM. Using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), we analyzed 34 GBMs that had also undergone molecular characterization as part of The Cancer Genome Atlas (TCGA). By IHC, 4 tumors (11.8%) had complete ...
The retinoblastoma tumor suppressor (Rb) acts in a conserved pathway that is deregulated in most human cancers. Inactivation of the single Rb-related gene in Caenorhabditis elegans, lin-35, has only limited effects on viability and fertility, yet causes changes in cell-fate and cell-cycle regulation when combined with inactivation of specific other genes. For instance, lin-35 Rb is a synthetic multivulva (synMuv) class B gene, which causes a multivulva phenotype when inactivated simultaneously with a class A or C synMuv gene. We used the ORFeome RNAi library to identify genes that interact with C. elegans lin-35 Rb and identified 57 genes that showed synthetic or enhanced RNAi phenotypes in lin-35 mutants as compared to rrf-3 and eri-1 RNAi hypersensitive mutants. Based on characterizations of a deletion allele, the synthetic lin-35 interactor zfp-2 was found to suppress RNAi and to cooperate with lin-35 Rb in somatic gonad development. Interestingly, ten splicing-related genes were found to function
To determine if replacement of the retinoblastoma (RB) tumor suppressor gene could inhibit invasion of RB-defective tumor cells, the capacity of tumor cells to migrate or invade was quantitated by the Boyden chamber assay. The studies were done in a diverse group of stable RB-reconstituted human tum …
It is widely believed that the cellular transcription factor DRTF1/E2F integrates cell cycle events with the transcription apparatus because during cell cycle progression in mammalian cells it interacts with molecules that are important regulators of cellular proliferation, suck as the retinoblastoma tumour suppressor gene product (pRb), p107, cyclins and cyclin-dependent kinases. Thus, pRb, which negatively regulates early cell cycle progression and is frequently mutated in tumour cells, and the Rb-related protein p107, bind to and repress the transcriptional activity of DRTF1/E2F. Viral oncoproteins, such as adenovirus E1a and SV40 large T antigen, overcome such repression by sequestering pRb and p107 and in so doing are likely to activate genes regulated by DRTF1/E2F, such as cdc2, c-myc and DHFR. Two sequence-specific DNA binding proteins, E2F-1 and DP-1, which bind to the E2F site, contain a small region of similarity. The functional relationship between them has, however, been unclear. We report
Cyclin D-Cdk4 complexes have a demonstrated role in G1 phase, regulating the function of the retinoblastoma susceptibility gene product (Rb). Previously, we have shown that following treatment with low doses of UV radiation, cell lines that express wild-type p16 and Cdk4 responded with a G2 phase cell cycle delay. The UV-responsive lines contained elevated levels of p16 post-treatment, and the accumulation of p16 correlated with the G2 delay. Here we report that in UV-irradiated HeLa and A2058 cells, p16 bound Cdk4 and Cdk6 complexes with increased avidity and inhibited a cyclin D3-Cdk4 complex normally activated in late S/early G2 phase. Activation of this complex was correlated with the caffeine-induced release from the UV-induced G2 delay and a decrease in the level of p16 bound to Cdk4. Finally, overexpression of a dominant-negative mutant of Cdk4 blocked cells in G2 phase. These data indicate that the cyclin D3-Cdk4 activity is necessary for cell cycle progression through G2 phase into mitosis and
The overall size of a metazoan is controlled at the cellular level by the coordinate regulation of cell division and cell growth. Although it has long been established that inappropriate cell division can lead to cancer, it is becoming increasingly clear that cell growth, or increase in cell mass, is of equal importance. For example, the oncogenes Myc, Ras and Cyclin D (Prober and Edgar, 2001) and the tumor suppressors retinoblastoma (White, 1997) and Pten (Gao et al., 2000; Goberdhan et al., 1999; Huang et al., 1999) have all been shown to regulate cell growth. Although the factors that regulate cell division have been extensively studied (Sherr and Roberts, 1999), the processes that control cell growth are just beginning to be elucidated (Stocker and Hafen, 2000).. Given the dependence of cell growth on protein synthesis, regulation of translation is likely to play an important role in growth control. In fact, recent studies have shown that one mechanism of cell growth regulation is achieved ...
TY - JOUR. T1 - Transforming growth factor β1 (TGF-β1) inhibits retinoblastoma gene expression but not pRB phosphorylation in TGF-β1-growth stimulated colon carcinoma cells. AU - Yan, Z.. AU - Hsu, Stephen. AU - Winawer, S.. AU - Friedman, E.. PY - 1992/1/1. Y1 - 1992/1/1. N2 - The response of the retinoblastoma (RB) gene and its product (pRB) to transforming growth factor β1 (TGF-β1) was studied in three types of colon carcinoma cells derived from the same parental line. TGF-β1 was a growth inhibitor for two enterocytic-differentiated lines, a growth stimulator for two undifferentiated lines, and had no effect on two goblet cell-differentiated lines. TGF-β1 treatment for 3 days decreased RB gene expression and pRB level two- to threefold in each responsive line. When treated with TGF-β1 beginning in early G1, enterocytic cells were arrested in G1 and pRB remained underphosphorylated and in low abundance. Neither goblet cell line exhibited these responses to TGF-β1 because they were ...
Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) and adventitial fibroblasts play an important role in the pathobiology of vascular occlusive disease (eg, atherosclerosis, in-stent restenosis, transplant vasculopathy, and vessel bypass graft failure).1,2 Thus, understanding the molecular mechanisms that control hyperplastic growth and the locomotion of vascular cells should aid in the development of novel therapeutic strategies to reduce neointimal thickening.. Cell cycle progression is controlled by several cyclin-dependent kinases (CDKs) that associate with regulatory cyclins.3 Mitogenic stimuli activate CDK/cyclin holoenzymes, thus causing hyperphosphorylation of the retinoblastoma protein (pRb) and related pocket proteins from mid G1 to mitosis. CDK-dependent pRb hyperphosphorylation releases E2F transcription factors, thus contributing to the expression of several growth and cell cycle-regulatory genes with functional E2F-binding sites in their ...
TY - JOUR. T1 - Historic Review of Retinoblastoma. AU - Albert, Daniel. PY - 1987/1/1. Y1 - 1987/1/1. N2 - Retinoblastoma was first described as a specific entity by James Wardrop in 1809, with enucleation as his suggested treatment. Histologic studies including those of Flexner and Verhoeff and subsequent electron microscopy have given insights into its pathogenesis. The establishment of cell lines of retinoblastoma, the nude mouse model, and other animal models have contributed additional information. Classic genetic and epidemiologic studies have led to a broad and intense interest in the tumor despite its relative infrequency. Attempts now in progress to identify and characterize the oncogene for retinoblastoma may prove to be the most exciting part of the history of retinoblastoma.. AB - Retinoblastoma was first described as a specific entity by James Wardrop in 1809, with enucleation as his suggested treatment. Histologic studies including those of Flexner and Verhoeff and subsequent ...
Retinoblastoma is a rare cancer of the eye that typically affects children between birth and five years of age. The incidence of Retinoblastoma is one in 15,000 live births, with about 23 children being affected in Canada each year.. It is imperative that Retinoblastoma is diagnosed at an early stage. Some of the signs of Retinoblastoma include a white pupil, eye turn, or a wondering eye. An eye exam at 6 month of age and then age at 3 years of age (and every year after that) is recommended to rule-out Retinoblastoma.. Read More:. http://doctorsofoptometry.ca/retinoblastoma/. ...
Reintroduction or reactivation of pRb in human tumor cell lines that lack functional pRb often results in senescence. In this study we have investigated the contribution of pRb to senescence by reintroducing RB into an osteosarcoma tumor cell line mutated for both RB and p53. In doing so we examined the transient and prolonged effects of pRb on cell cycle protein levels and activities, cellular proliferation, and cellular morphology and the importance of these changes in cellular function to senescence. We found that soon after pRb expression, p27KIP1 synthesis increased in an E2F-independent manner, cyclin E-cdk2 kinase activity decreased, and the cells arrested in the G1 phase. These properties persisted upon prolonged pRb expression and progression into the senescent state, suggesting that they are important in the senescence process.. Most significantly, we found that only pRb and not p107 or p130 could induce sustained p27KIP1 synthesis and senescence, despite the fact that p107 and p130 ...
Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug
Aberrant cytoplasmic accumulation of retinoblastoma protein in basal cells may lead to increased survival in malignant canine mammary tumours S.. Gupta Guru Angad Dev Veterinary and
Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Genetic alterations affecting p16INK4a and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein (RB) and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development. Like the tumor suppressor protein p53, components of this RB pathway, although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life.. ...
Although it has not been widely studied, but in fact it contains a class of potential anticancer compounds, such as alkaloids and flavonoids, both of which are potentially as negative regulators of oncogenes (cell cycle regulatory genes group) and tumor suppressor gene positive regulator, so that potential as anti-cancer (Shapiro and Harper, 1999). Negative regulation of oncogenes will stop the proliferation of cancer cells in a specific phase of the cell cycle. As tumor suppressor genes, such as p53 and protein Retinoblastoma protein (PRB). Rb protein is able to bind to E2F proteins (replication factor), so that the cell cycle would be inhibited (Gibbs, 2000). For example alkaloids, on the vinca (Chatarathus roseus (L.) G. Don) were able to stop the cancer cells in metaphase of mitosis (Irna, 2001). While flavonoids can induce apoptosis through inhibition of the activity of DNA Topoisomerase I / II, a decrease in ROS (Reactive Oxygen Species), release of cytochrome C, endonuclease activation ...
Retinoblastoma is a malignant tumor of the developing retinal cells caused in most cases by mutations in both copies of the RB1 gene. The RB1 gene is a tumor suppressor gene, located on chromosome 13q14 and is the first human cancer gene to be cloned. The gene codes for the tumor suppressor protein pRB, which by binding to the transcription factor E2F, inhibits the cell from entering the S-phase during mitosis. Recent evidence suggests that post-mitotic cone precursors are uniquely sensitive to pRB depletion and may be the cells in which retinoblastoma originates.. However, more recent information suggests that the occurrence and viability of retinoblastic cells may be more complex than suggested by simple loss of function of the RB1 alleles. There is increasing evidence for the role of epigenetic factors such as DNA methylation impacting the differential expression of more than 100 additional genes which may be influencing the retinoblastoma phenotype. Among these is an upregulation of spleen ...
Serine/arginine-rich splicing factors (SRSFs) play wide-ranging roles in gene expression through post-transcriptional regulation as well as pre-mRNA splicing. SRSF7 was highly expressed in colon cancer tissues, and its knockdown inhibited cell growth in colon cancer cells (HCT116) in association with altered expression of 4,499 genes. The Ingenuity Pathway Analysis revealed that cell cycle-related canonical pathways were ranked as the highly enriched category in the affected genes. Western blotting confirmed that p21, a master regulator in cell cycle, was increased without any induction of p53 in SRSF7 knockdown cells. Furthermore, cyclin-dependent kinase 2 and retinoblastoma protein were remained in the hypophosphorylated state. In addition, the SRSF7 knockdown-induced cell growth inhibition was observed in p53-null HCT116 cells, suggesting that p53-independent pathways were involved in the SRSF7 knockdown-induced cell growth inhibition. The reduction of SRSF7 stabilized cyclin-dependent kinase ...
p16(INK4a) acts to block cell cycle progression by binding to cyclin-dependent kinase-4 (CDK4) and CDK6 and inhibiting the catalytic activity of the CDK4-CDK6/cyclin D complex required for retinoblastoma protein phosphorylation (1, 2). p16(INK4a) blocks progression beyond the G1-S restriction point by disrupting the formation of an E2F-DB active transcriptional complexes, thereby preventing the transcription of cell cycle progression genes (3). Loss or inactivation of p16(INK4a) function has been observed in numerous tumor types (4-6), and p16(INK4a) has been implicated to play an important role in the control of replicative senescence in fibroblasts and human mammary epithelial cells (7, 8).. Loss of p16(INK4a) function has been identified to be the result of both genetic and epigenetic events. Multiple mechanisms exist, including point mutation, loss of heterozygosity (LOH), small homozygous deletion (,200 kb), and promoter hypermethylation. LOH at the INK4a/ARF locus (9p21) has been reported ...
The oncogenes of the small DNA tumor viruses encode transforming proteins with multiple domains that influence the cell cycle and aspects of the transformed phenotype. Like other gene products of this type, the adenovirus E1A proteins influence the cell by binding to specific cell growth control proteins. These include members of the retinoblastoma gene product (pRB) family, which are bound by the E1A region 2-specific site, and p300, which is bound at the E1A amino terminus. Binding at these two sites is largely independent, and discrete transcription-regulating functions remain intact in E1A products when only one or the other binding site is functional. In this report, immunoprecipitation with p300 antibodies reveals the presence of the pRB family proteins in p300 complexes when E1A is expressed in host cells, indicating that E1A can mediate physical contact between p300 and the pRB-related proteins. The ability of E1A to induce proliferation efficiently in quiescent primary cells correlates ...
Scientists have developed a new locally applied treatment for retinoblastoma, a childhood cancer of the eye arising from immature retinal cells in one or both eyes and can developed from anytime between gestation until up to 5 years of age. This relatively uncommon condition affects about 1 out of every 15,000 live births, or about 250-300 children in the US each year.. Based on the theory that a molecule called MDMX prevents apoptosis or programmed cell death in retinoblastoma cancer, scientists used a combination of nutlin-3, which blocks MDMX and topotecan, another retinoblastoma drug candidate. Local delivery of the two-drug combo was found to be effective, reducing tumor size significantly more than the most effective known combination of standard chemotherapy drugslinks.. Our finding with locally applied nutlin-3 also has major implications for certain forms of adult cancers, since some forms of breast, lung, prostate and colon cancer are caused by abnormally large quantities of MDMX, ...
Today we continue with Part II of Living With Retinoblastoma, a fast growing eye-cancer which affects babies and young children. Retinoblastoma affects about 1 in 15, 000 live births, and an estimated 9,000 children develop the cancer globally each year. These posts cover living with retinoblastoma for those who have either had treatment for or…
The retinoblastoma protein: Rb) inhibits both cell division and apoptosis, but the mechanism by which Rb alternatively regulates these divergent outcomes remains poorly understood. Cyclin dependent kinases: Cdks) promote cell division by phosphorylating and reversibly inactivating Rb by a hierarchical series of phosphorylation events and sequential conformational changes. The stress-regulated mitogen activated protein kinase: MAPK) p38 also phosphorylates Rb, but it does so in a cell cycle-independent manner that is associated with apoptosis rather than with cell division. Here, we show that p38 phosphorylates Rb by a novel mechanism that is distinct from that of Cdks. p38 bypasses the cell cycle-associated hierarchical phosphorylation and directly phosphorylates Rb on Ser567, which is not phosphorylated during the normal cell cycle. Phosphorylation by p38, but not Cdks, triggers an interaction between Rb and the human homologue of murine double minute 2: Hdm2), leading to degradation of Rb, release of
October 12, 2017 Retinoblastoma is a tumor of the retina that usually impacts kids below 5 years of age. If not identified early, retinoblastoma could lead
Researchers have found a non-invasive way to biopsy retinoblastoma tumors, which could enable precision therapies for children with the rare cancer.
Retinoblastoma is caused by a mutation in a gene that controls how cells divide. As a result, cells grow out of control and become cancerous.. In about half the cases, this mutation develops in a child whose family has never had eye cancer. In other cases, the mutation occurs in several family members. If the mutation runs in the family, there is a 50% chance that an affected persons children will also have the mutation. These children will therefore have a high risk of developing retinoblastoma themselves.. The cancer most often affects children younger than 7 years old. It is most commonly diagnosed in children 1 to 2 years old. ...
Hey There, Helen and mommy Siobahn here again - today we are going to continue with Helens Story because we want everyone out there to know about Childhood Cancer and about my cancer, Retinoblastoma. Now that the problem had been diagnosed as Retinoblastoma, things moved along very quickly. The diagnosis was made on the Thursday…
Retinoblastoma is a rare cancer of the retina of the eye. The retina is in the back of the eye. Its the part of the eye that receives light. Retinoblastoma is the most common tumor affecting the eye in children. It almost always occurs in children less than 5 years old.
Retinoblastoma is an uncommon cancer of the eye which occurs in children under the age of 5. This leaflet describes retinoblastoma. It discusses the symptoms...
Looking for medication to treat retinoblastoma? Find a list of current medications, their possible side effects, dosage, and efficacy when used to treat or reduce the symptoms of retinoblastoma
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The most widely held concept of histogenesis of retinoblastoma holds that it generally arises from a multipotential precursor cell (mutation in the long arm of chromosome 13 band 13q14) that could develop into almost any type of inner or outer retinal cell. Intraocularly, it exhibits a variety of growth patterns, which have been described as ...
Retinoblastoma is a malignant tumour that originates from cone precursors of the developing retina and is usually diagnosed in children under age of 5 years
The most widely held concept of histogenesis of retinoblastoma holds that it generally arises from a multipotential precursor cell (mutation in the long arm of chromosome 13 band 13q14) that could develop into almost any type of inner or outer retinal cell. Intraocularly, it exhibits a variety of growth patterns, which have been described as ...
Retinoblastoma is a childhood cancer that affects the retina, the area of the eye responsible for sensing light and sending nerve signals to the brain.
In case of symptoms or an abnormal test, more testing can help find out if its cancer. Learn about retinoblastoma diagnosis tests here.
Retinoblastoma - Etiology, pathophysiology, symptoms, signs, diagnosis & prognosis from the MSD Manuals - Medical Professional Version.
Whether your child has just been diagnosed with retinoblastoma, is going through treatment, or is trying to stay well after treatment, this detailed guide can help you find the answers you need.
The retinoblastoma protein inhibits cancer by controlling cell division. Now, researchers have shown that it also binds to and inhibits genes necessary for pluripotency - a defining characteristic of stem cells.
The retinoblastoma protein inhibits cancer by controlling cell division. Now, researchers have shown that it also binds to and inhibits genes necessary for pluripotency - a defining characteristic of stem cells.
Using the gene networks and other computational tools, weve now gained some ability to rationally predict the consequences to an organism of mutating or interrupting a specific gene. This means that by using these tools, we can often select a small set of candidate genes to be implicated in a particular disease or trait. Weve now experimentally validated ,100 such candidate genes for diverse traits in a wide range of organisms, including yeast, worms, Arabidopsis, C. elegans, frogs, mice, and humans. For example, in yeast weve used network models to discovery a large number of new ribosome biogenesis genes, as well as genes controlling such features as cell size. In animals, e.g. using our worm gene network models, we could successfully identify new genes controlling longevity, as well as genes capable of suppressing the loss of the Retinoblastoma tumor suppressor, thus curing worms of model tumors. In plants, with now ex-postdoc Insuk Lee and collaborator Sue Rhee, we could rationally ...
Using the gene networks and other computational tools, weve now gained some ability to rationally predict the consequences to an organism of mutating or interrupting a specific gene. This means that by using these tools, we can often select a small set of candidate genes to be implicated in a particular disease or trait. Weve now experimentally validated ,100 such candidate genes for diverse traits in a wide range of organisms, including yeast, worms, Arabidopsis, C. elegans, frogs, mice, and humans. For example, in yeast weve used network models to discovery a large number of new ribosome biogenesis genes, as well as genes controlling such features as cell size. In animals, e.g. using our worm gene network models, we could successfully identify new genes controlling longevity, as well as genes capable of suppressing the loss of the Retinoblastoma tumor suppressor, thus curing worms of model tumors. In plants, with now ex-postdoc Insuk Lee and collaborator Sue Rhee, we could rationally ...
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