Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Open accessAbstract
Advanced human cancers are invariably aneuploid, in that they harbour cells with abnormal chromosome numbers. However, the molecular defects underlying this trait, and whether they are a cause or a consequence of the malignant phenotype, are not clear. Mutations that disable the retinoblastoma (Rb) pathway are also common in human cancers. These mutations promote tumour development by deregulating the E2F family of transcription factors leading to uncontrolled cell cycle progression. We show that the mitotic checkpoint protein Mad2 is a direct E2F target and, as a consequence, is aberrantly expressed in cells with Rb pathway defects. Concordantly, Mad2 is overexpressed in several tumour types, where it correlates with high E2F activity and poor patient prognosis. Generation of Rb pathway lesions in normal and transformed cells produces aberrant Mad2 expression and mitotic defects leading to aneuploidy, such that elevated Mad2 contributes directly to these defects. These results demonstrate how chromosome instability can arise as a by-product of defects in cell cycle control that compromise the accuracy of mitosis, and suggest a new model to explain the frequent appearance of aneuploidy in human cancer.
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TL;DR
This paper argues that loss of Rb pathway control deregulates E2F, causing abnormal Mad2 expression that disrupts mitosis and produces aneuploidy. It proposes that chromosome instability in cancer can be an unintended consequence of cell-cycle defects rather than only a selected malignant trait.
Key findings
- Mad2 is transcriptionally regulated by E2F: E1A, E2F-1, and Rb loss increased Mad2 in fibroblasts, E2F-1 bound the MAD2 promoter by ChIP, and a MAD2 promoter fragment conferred E2F responsiveness in reporter assays.
- Mad2 was overexpressed in human tumors with Rb pathway defects, including retinoblastoma and advanced bladder carcinoma; in 106 neuroblastoma tumors and 12 cell lines, MAD2 mRNA correlated with E2F1 mRNA (Kendall tau = 0.568, P < 0.0001), and high MAD2 was associated with worse survival (P = 0.001) more strongly than MYCN amplification (P = 0.0215).
- E1A, shRb, or MAD2 expression in IMR90/NIH-3T3/HCT116 cells caused >4c DNA content, abnormal chromosome numbers by FISH and metaphase counting, prolonged mitosis, cytokinesis defects, and chromosome segregation errors.
- Partial Mad2 knockdown in E2F- or E1A-expressing HCT116 cells reduced aneuploidy (e.g., P = 0.015 and P < 0.0001 for E2F plus shMAD2A versus control at 0 and 12 h nocodazole; P = 0.006 and P = 0.0007 for shMAD2B), supporting a causal role for elevated Mad2.
Methods
- Cell-based study using human tumor lines (T24, HT1197, HCT116, SW480, U-2OS), normal human fibroblasts (IMR90), murine NIH-3T3 cells, and primary MEFs; retroviral or adenoviral delivery of E1A, E2F-1, shRb, shMAD2, control shRNA, or MAD2 cDNA, with puromycin selection and nocodazole treatment.
- Molecular and cytogenetic assays included northern and western blotting, ChIP, luciferase reporters, laser scanning cytometry, FACS, BrdU incorporation, FISH for chromosomes 1 and 17, metaphase chromosome counting, H2B-GFP videomicroscopy, and immunohistochemistry.
- Human sample analysis included 12 retinoblastoma cases, 95 bladder tumors on a tissue array, 106 neuroblastoma tumors plus 12 neuroblastoma cell lines by Affymetrix U95 arrays, and validation on a 50-case neuroblastoma tissue microarray; correlations used Kendall’s tau, Kaplan-Meier curves, and log-rank tests.
Limitations
- The paper does not present a formal limitations section. It notes that other Rb targets may also contribute to chromosome instability, although it argues aberrant Mad2 is important.
- The text observes that the frequency of aberrant mitoses declined after serial passaging, possibly due to death of cells with abnormal chromosome content or adaptation to elevated Mad2.
- The text reports no centrosome amplification in E1A- or MAD2-transduced fibroblasts, but suggests cyclin E–driven centrosome duplication could still worsen instability after Rb loss; much of the causal evidence comes from cultured cells, with human tumor data largely correlative.
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- Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
A MAD2 genomic fragment containing the E2F sites conferred E2F responsiveness to a luciferase reporter in U-2OS cells, comparable to the caspase-7 promoter.
“a MAD2 genomic fragment containing the E2F sites (Supplementary Fig. S1) conferred E2F responsiveness to a luciferase reporter following transient transfection into IMR90 (data not shown) or U-2OS cells (Fig. 1d) in a manner comparable to the caspase-7 promoter, an established E2F target 15 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Nahlé, Z. et al. Direct coupling of the cell cycle and cell death machinery by E2F. Nature Cell Biol. 4, 859–864 (2002) source
Not checked in the free run.
- Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
E1A-, shRB- and MAD2-transduced IMR90 or NIH-3T3 populations accumulated cells with greater than 4c DNA content during cell division.
“Biparametric LSC analysis comparing BrdU incorporation and DNA content demonstrated that E1A-, shRB-and MAD2-transduced IMR90 or NIH-3T3 cell populations accumulated cells with greater than 4c DNA content during the course of cell division (Fig. 4a).”
Quote in the paperSubstantial claim - Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
High Mad2 expression is more tightly associated with survival than MYCN amplification (P=0.001 for MAD2; P=0.0215 for MYCN).
“In fact, high Mad2 expression was more tightly associated with survival than MYCN amplification (P ¼ 0.001 for MAD2; P ¼ 0.0215 for MYCN).”
Quote in the paperSubstantial claim - Findingreasoning§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
In each cell population, the frequency of aberrant mitoses decayed after serial passaging.
“In each cell population, the frequency of aberrant mitoses decayed after serial passaging, perhaps owing to lethality of cells with aberrant chromosome content and/or to cellular adaptation to elevated Mad2.”
Quote in the paperNot a substantial claim - Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Retinoblastomas express high levels of Mad2 relative to normal retina.
“Retinoblastomas, which invariably lose Rb function and deregulate E2F, expressed high levels of Mad2 relative to normal retina (Fig. 3a, upper panels).”
Quote in the paperSubstantial claim- Rests on an assumption: Retinoblastomas invariably lose Rb function and deregulate E2F.
- Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
IMR90 human fibroblasts expressing E1A or E2F-1 have elevated Mad2 levels.
“IMR90 human fibroblasts expressing either E1A (Fig. 1b, compare lanes 1 and 2) or E2F-1 (Fig. 1b, compare lanes 1 and 3) also expressed elevated Mad2 levels”
Quote in the paperSubstantial claim - Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
MEFs from Rb-/- mice have increased Mad2 levels compared with Rb+/+ controls.
“Similarly, MEFs isolated from Rb 2/2 mice displayed increased Mad2 levels compared to Rb þ/þ controls (Fig. 1a, compare lanes 5 and 6).”
Quote in the paperSubstantial claim - Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Chromosome counting of metaphase spreads confirmed that IMR90 and HCT116 cells with defective Rb or elevated Mad2 are frequently aneuploid.
“Chromosome counting of metaphase spreads confirmed that IMR90 and HCT116 cells with defective Rb or elevated Mad2 are frequently aneuploid (Fig. 4c).”
Quote in the paperSubstantial claim - Findingcitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Mad2 is significantly increased in many bladder carcinomas compared with normal urothelium, particularly in more advanced tumours.
“Similarly, Mad2 was significantly increased in many bladder carcinomas when compared to normal urothelium (data not shown), particularly in the more advanced tumours, where Rb inactivation is common 19 (Fig. 3a, middle panels).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Dalbagni, G., Presti, J., Reuter, V., Fair, W. R. & Cordon-Cardo, C. Genetic alterations in bladder cancer. Lancet 324, 469–471 (1993) source
Not checked in the free run.
- Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Cells aberrantly expressing Mad2 displayed a delay in the degradation of securin and cyclin B.
“Nevertheless, consistent with a prolonged mitosis, cells aberrantly expressing Mad2 displayed a delay in the degradation of securin and cyclin B (Supplementary Fig. S4b, c)”
Quote in the paperNot a substantial claim - Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Mad2 levels in E1A- and shRb-expressing IMR90 cells are similar to those produced by enforced MAD2 expression.
“Of note, Mad2 levels in E1A-and shRb-expressing IMR90 cells were similar to those produced by enforced expression of MAD2 (Fig. 2b, c).”
Quote in the paperSubstantial claim - Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
The increase in Mad2 is confined largely to mitosis.
“The increase in Mad2 was confined largely to mitosis, as assessed by coexpression with phosphorylated histone H3 following release from a double-thymidine-induced S-phase arrest (Fig. 1f), and by laser scanning cytometry (LSC) analysis of Mad2 expression in unsynchronized NIH-3T3 fibroblasts (Fig. 1g).”
Quote in the paperNot a substantial claim - Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
The MAD2 genomic sequence contains several putative E2F-binding sites in its promoter.
“analysis of the MAD2 genomic sequence showed several putative E2F-binding sites in the MAD2 promoter (see Supplementary Fig. S1)”
Quote in the paperSubstantial claim - Findingcitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
In neuroblastoma, MAD2 mRNA levels correlate tightly with E2F1 mRNA expression (Kendall tau 0.568; P<0.0001) across 106 tumours and 12 cell lines.
“Here, MAD2 messenger RNA levels correlated tightly with E2F1 mRNA expression (an E2F member but also a prototypical E2F target gene), as shown by analysis of a microarray database containing information on 106 neuroblastoma tumours and 12 neuroblastoma cell lines 20 (Fig. 3b; Kendall tau correlation coefficient: 0.568; P , 0.0001)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Alaminos, M. et al. Genome-wide analysis of gene expression associated with MYCN in human neuroblastoma. Cancer Res. 63, 4538–4546 (2003)
Not checked in the free run.
- Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
ChIP analysis confirmed in vivo binding of E2F-1 to the predicted sites in E1A-expressing cells.
“subsequent chromatin immunoprecipitation (ChIP) analysis confirmed in vivo binding of E2F-1 to their predicted sites in E1Aexpressing cells (Fig. 1c, lane 2).”
Quote in the paperSubstantial claim - Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Elevated Mad2 levels in human tumours are not merely due to increased proliferation of cancer cells.
“The elevated Mad2 levels observed in human tumours were not merely due to the increased proliferation of cancer cells, as Mad2 was not always detected in highly proliferating normal and tumour samples (see Supplementary Fig. S2).”
Quote in the paperSubstantial claim - Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
E1A significantly increased MAD2 expression in microarray experiments.
“we observed that E1A significantly increased the expression of MAD2 (Z.N., V.M. and S.W.L., unpublished observations)”
Quote in the paperSubstantial claim - Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
No centrosome amplification was detected in E1A- or MAD2-transduced fibroblasts by gamma-tubulin or beta-tubulin immunofluorescence.
“No centrosome amplification was detected in E1A-or MAD2transduced fibroblasts by g-tubulin (see Supplementary Fig. S3b) or b-tubulin immunofluorescence staining (spindle shape analysis; data not shown)”
Quote in the paperSubstantial claim - Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Northern and western blot analyses confirmed that E1A upregulates MAD2 transcript and protein in mouse embryo fibroblasts.
“Northern and western blot analyses of MAD2 transcript and protein confirmed its upregulation by E1A in mouse embryo fibroblasts (MEFs) (Fig. 1a, compare lanes 1 and 2 or 3 and 4, respectively).”
Quote in the paperSubstantial claim - Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Advanced human cancers are aneuploid, containing cells with abnormal chromosome numbers.
“Advanced human cancers are invariably aneuploid, in that they harbour cells with abnormal chromosome numbers 1,2 .”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Previous global ChIP/microarray studies suggested that E2Fs can bind the MAD2 promoter in normal fibroblasts.
“Concordantly, previous global chromatin immunoprecipitation/microarray studies suggested that E2Fs can bind the MAD2 promoter in normal fibroblasts 14 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Ren, B. et al. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev. 16, 245–256 (2002) source
Not checked in the free run.
- Interpretationown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Deregulation of the Rb/E2F pathway induces Mad2 through a conserved mechanism.
“implying that deregulation of the Rb/E2F pathway induces Mad2 through a conserved mechanism.”
Quote in the paperSubstantial claim - Interpretationown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Mad2 is a direct E2F target.
“We show that the mitotic checkpoint protein Mad2 is a direct E2F target and, as a consequence, is aberrantly expressed in cells with Rb pathway defects.”
Quote in the paperSubstantial claim - Interpretationown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Cells with Rb defects often aberrantly express Mad2.
“Thus, cells with Rb defects often aberrantly express Mad2.”
Quote in the paperSubstantial claim - Interpretationown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Rb pathway lesions in normal and transformed cells produce aberrant Mad2 expression and mitotic defects that lead to aneuploidy.
“Generation of Rb pathway lesions in normal and transformed cells produces aberrant Mad2 expression and mitotic defects leading to aneuploidy, such that elevated Mad2 contributes directly to these defects.”
Quote in the paperSubstantial claim - Interpretationown data
Persistent inactivation of the APC/cyclosome mediated by Mad2 signalling delays the degradation of securin and cyclin B.
“Persistent inactivation of the APC/ cyclosome, mediated by Mad2 signalling, delays the degradation of securin and cyclin B.”
Quote in the paperSubstantial claim - Interpretationreasoning
During normal cell proliferation, the cell cycle is hardwired to the spindle checkpoint through E2F, ensuring that Mad2 expression is tightly controlled.
“During normal cell proliferation, the cell cycle is hardwired to letters to nature the spindle checkpoint through E2F, presumably to ensure that Mad2 expression is tightly controlled.”
Quote in the paperSubstantial claim - Premisecitation
Complete downregulation of Mad2 in cells with intact Rb produces aneuploidy after a premature anaphase.
“Complete downregulation of Mad2 in cells with intact Rb produces aneuploidy after a premature anaphase 27 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Michel, L. et al. Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells. Proc. Natl Acad. Sci. USA 101, 4459–4464 (2004) source
Not checked in the free run.
- Interpretationreasoning§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Mad2 is aberrantly expressed in cells with Rb pathway defects.
“We show that the mitotic checkpoint protein Mad2 is a direct E2F target and, as a consequence, is aberrantly expressed in cells with Rb pathway defects.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Elevated Mad2 contributes directly to the mitotic defects and aneuploidy caused by Rb pathway lesions.
“Generation of Rb pathway lesions in normal and transformed cells produces aberrant Mad2 expression and mitotic defects leading to aneuploidy, such that elevated Mad2 contributes directly to these defects.”
Quote in the paperSubstantial claim - Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Rb inactivation is common in advanced bladder tumours.
“particularly in the more advanced tumours, where Rb inactivation is common 19”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Dalbagni, G., Presti, J., Reuter, V., Fair, W. R. & Cordon-Cardo, C. Genetic alterations in bladder cancer. Lancet 324, 469–471 (1993) source
Not checked in the free run.
- Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
T24 is Rb-functional.
“Rb-functional T24 bladder carcinoma 17”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Sanchez-Carbayo, M. et al. Molecular profiling of bladder cancer using cDNA microarrays: defining histogenesis and biological phenotypes. Cancer Res. 62, 6973–6980 (2002)
Not checked in the free run.
- Interpretationown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
MAD2 is a physiological transcriptional target of E2F.
“Therefore, MAD2 is a physiological transcriptional target of E2F.”
Quote in the paperSubstantial claim - Interpretationown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Misexpression of Mad2 is sufficient to produce the chromosomal instability phenotype.
“Nevertheless, misexpression of Mad2 is sufficient to produce this phenotype.”
Quote in the paperSubstantial claim - Interpretationown data
Aberrant Mad2 activity is important for chromosome instability in Rb-defective cells.
“Therefore, although other Rb targets may contribute to chromosome instability, aberrant Mad2 activity is important for this process.”
Quote in the paperSubstantial claim - Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Loss-of-function mutations in spindle checkpoint genes are rarely observed in human tumours.
“loss-of-function mutations in spindle checkpoint genes are rarely observed in human tumours 11,12 .”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [11] Cahill, D. P. et al. Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics 58, 181–187 (1999) source
Not checked in the free run.
- cites [12] Hernando, E. et al. Molecular analyses of the mitotic checkpoint components hsMAD2, hBUB1 and hBUB3 in human cancer. Int. J. Cancer 95, 223–227 (2001) source
Not checked in the free run.
- Interpretationown data
Aneuploidy in human cancers can arise as a byproduct of the Rb pathway defects that accompany tumorigenesis.
“Our data illustrate how aneuploidy in human cancers can arise as a byproduct of the Rb pathway defects that accompany tumorigenesis.”
Quote in the paperSubstantial claim - Interpretationreasoning
Deregulated Mad2 expression contributes to mitotic alterations and chromosome instability in the context of an altered Rb/E2F pathway.
“Together, our results demonstrate that deregulated Mad2 expression contributes to mitotic alterations and chromosome instability in the context of an altered Rb/E2F pathway.”
Quote in the paperSubstantial claim - Interpretationown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control
Chromosome instability can arise as a byproduct of defects in cell cycle control that compromise the accuracy of mitosis.
“These results demonstrate how chromosome instability can arise as a byproduct of defects in cell cycle control that compromise the accuracy of mitosis, and suggest a new model to explain the frequent appearance of aneuploidy in human cancer.”
Quote in the paperSubstantial claim - Interpretationreasoning
The results provide one explanation for why loss-of-function mutations in spindle checkpoint genes are uncommon in human cancers.
“Hence, our results provide one explanation for why loss-of-function mutations in spindle checkpoint genes are uncommon in human cancers 11,12 .”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [11] Cahill, D. P. et al. Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics 58, 181–187 (1999) source
Not checked in the free run.
- cites [12] Hernando, E. et al. Molecular analyses of the mitotic checkpoint components hsMAD2, hBUB1 and hBUB3 in human cancer. Int. J. Cancer 95, 223–227 (2001) source
Not checked in the free run.
- May combine two claims. 20
- Classified as probably not a substantial claim. 13
May combine two claims.
Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlAberrant Mad2 expression is associated with MYCN overexpression and amplification and with poor patient prognosis in neuroblastoma.
“Moreover, aberrant Mad2 expression was associated with MYCN (a protooncogene of the myelocytomatosis (MYC)-box genes) overexpression and amplification (which can drive E2F constitutive activation 21 ) and poor patient prognosis (Fig. 3c).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Schuldiner, O. & Benvenisty, N. A DNA microarray screen for genes involved in c-MYC and N-MYC oncogenesis in human tumors. Oncogene 20, 4984–4994 (2001) source
Not checked in the free run.
May combine two claims.
Findingown dataCo-expression of shMAD2 with E2F or E1A significantly reduced Mad2 to nearly normal levels and reduced the fraction of aneuploid cells without affecting E1A or E2F-1 levels.
“In contrast, co-expression of shMAD2 with E2F or E1A significantly reduced Mad2 to nearly normal levels (Fig. 5d, compare lanes 3 with 7 or 2 with 8) and reduced the fraction of aneuploid cells (Fig. 5e, f) without affecting E1A or E2F-1 levels (Supplementary Fig. S4d).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationStable expression of two independent shMAD2 hairpins in cells with low Mad2 levels further reduced Mad2 expression and increased the percentage of aneuploid cells.
“Consistent with a previous report 27 , stable expression of two independent short-hairpin RNAs (shMAD2) in cells with low Mad2 levels further reduced Mad2 expression and increased the percentage of aneuploid cells (data not shown).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Michel, L. et al. Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells. Proc. Natl Acad. Sci. USA 101, 4459–4464 (2004) source
Not checked in the free run.
May combine two claims.
Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlMad2 is expressed at aberrantly high levels throughout the cell cycle in IMR90 cells expressing E1A and in cells with Rb suppressed by RNAi.
“Concordantly, Mad2 was expressed at aberrantly high levels throughout the cell cycle in IMR90 cells expressing E1A (Fig. 2a), which deregulates endogenous E2F, and in cells where Rb was suppressed by stable RNA interference (RNAi) (shRb 16 , Fig. 2a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716 (2003) source
Not checked in the free run.
May combine two claims.
Findingown dataCells coexpressing shMAD2 and either E2F-1 or E1A were proliferating and showed similar S phase content compared with cells harbouring a control shRNA.
“Cells coexpressing shMAD2 and either E2F-1 or E1A were proliferating and showed similar S phase content compared to cells harbouring a control shRNA (data not shown).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlCells expressing E1A or shRb took an unusually long time to finish mitosis, with difficulties in cytokinesis and frequent chromosome segregation defects.
“Whereas normal NIH-3T3 cells underwent an orderly and rapid mitosis, cells expressing E1A or shRb took an unusually long time to finish the process, displaying marked difficulties in completing cytokinesis (Fig. 5a-c; Supplementary Fig. S4a and S5, compare video A with C and D) and frequent defects in chromosome segregation (Fig. 5c; Supplementary Fig. S5, compare video B with G).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlIMR90 cells expressing control vector retained normal chromosome content upon serial passaging and responded normally to nocodazole.
“In contrast, IMR90 cells expressing a control vector retained normal chromosome content upon serial passaging (Fig. 4a-c, see Vector or V) and responded normally to nocodazole (data not shown).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlMad2 is undetectable in quiescent IMR90 cells and increases after S phase following serum addition, reaching maximum levels in G2/M slightly after cyclin A.
“The level of Mad2 was undetectable in quiescent IMR90 cells (Fig. 1e, t ¼ 0) and increased after cells entered S phase following serum addition, reaching maximum levels in G2/M, albeit slightly after cyclin A.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlCells expressing Mad2 alone displayed similar mitotic defects, with chromosome segregation abnormalities more pronounced.
“Cells expressing Mad2 alone displayed similar defects (Fig. 5c; Supplementary Fig. S5, compare video A with E and F), although the chromosome segregation abnormalities were more pronounced, perhaps owing to the higher Mad2 levels that these populations expressed (Supplementary Fig. S5, compare video B with H).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlE1A-, shRB- and MAD2-expressing populations each accumulated cells with aberrant chromosome numbers by FISH.
“The E1A-, shRB-and MAD2-expressing populations each accumulated cells with aberrant chromosome numbers (Fig. 4b, c).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlMutations that disable the Rb pathway are common in human cancers.
“Mutations that disable the retinoblastoma (Rb) pathway are also common in human cancers 1 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000) source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlMany studies suggest that aneuploidy arises from defects in the conserved spindle checkpoint that normally governs progression through mitosis.
“Many studies suggest that aneuploidy arises from defects in the conserved spindle checkpoint that normally governs progression through mitosis 4,5 .”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [4] Jallepalli, P. V. & Lengauer, C. Chromosome segregation and cancer: cutting through the mystery. Nature Rev. Cancer 1, 109–117 (2001) source
Not checked in the free run.
- cites [5] Cahill, D. P. et al. Mutations of mitotic checkpoint genes in human cancers. Nature 392, 300–303 (1998) source
Not checked in the free run.
May combine two claims.
Interpretationown dataAberrant expression of Mad2 arising from Rb pathway defects can produce a hyperactive spindle checkpoint, altering the sequence of mitotic events and the accuracy of chromosome transmission.
“We suggest that aberrant expression of Mad2 arising as a result of Rb pathway defects can produce a hyperactive spindle checkpoint, thereby altering the sequence of mitotic events and the accuracy of chromosome transmission.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlMad2 is a crucial spindle checkpoint component that associates with APC/cyclosome and prevents its activation.
“a crucial component of the spindle checkpoint that associates with the APC/cyclosome, and prevents its activation 7,13 .”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [7] Yu, H. Regulation of APC-Cdc20 by the spindle checkpoint. Curr. Opin. Cell Biol. 14, 706–714 (2002) source
Not checked in the free run.
- cites [13] Wassmann, K. & Benezra, R. Mad2 transiently associates with an APC/p55Cdc complex during mitosis. Proc. Natl Acad. Sci. USA 95, 11193–11198 (1998) source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCells treated for prolonged periods with nocodazole adapt and enter the next cell cycle without a proper mitosis.
“the behaviour of cells with aberrant Mad2 expression is reminiscent of cells treated for prolonged periods with nocodozole-following spindle checkpoint activation, these cells eventually adapt and enter the next cell cycle without a proper mitosis 29 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Lanni, J. S. & Jacks, T. Characterization of the p53-dependent postmitotic checkpoint following spindle disruption. Mol. Cell. Biol. 18, 1055–1064 (1998) source
Not checked in the free run.
May combine two claims.
Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlHT1197 and SW480 have inactive Rb.
“such as HT1197 (ref.17) and SW480 (ref.18), respectively”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [17] Sanchez-Carbayo, M. et al. Molecular profiling of bladder cancer using cDNA microarrays: defining histogenesis and biological phenotypes. Cancer Res. 62, 6973–6980 (2002)
Not checked in the free run.
- cites [18] Arber, N. et al. Antisense to cyclin D1 inhibits the growth and tumorigenicity of human colon cancer cells. Cancer Res. 57, 1569–1574 (1997)
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataTwo sequence-independent shMAD2 hairpins were used.
“two sequenceindependent hairpins, shMAD2A and shMAD2B”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationreasoning§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlAberrant Mad2 expression is linked to Rb pathway defects in human tumours, where it can be an effective indicator of patient prognosis.
“Therefore, aberrant Mad2 expression is linked to Rb pathway defects in human tumours, where it can be an effective indicator of patient prognosis.”
Quote in the paperSubstantial claim- Rests on an assumption: Retinoblastomas invariably lose Rb function and deregulate E2F.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationLSC analyses measured at least 3,000 cells per slide.
“A minimum of 3,000 cells were analysed per slide as previously described 30 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Darzynkiewicz, Z., Gong, J., Juan, G., Ardelt, B. & Traganos, F. Cytometry of cyclin proteins. Cytometry 25, 1–13 (1996) source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlIn response to lack of tension or improper microtubule attachment at kinetochores, sensor proteins release a diffusible signal that inhibits APC/cyclosome ubiquitin ligase activity.
“In response to lack of tension or improper microtubule attachment at the kinetochores, a group of sensor proteins (Bub3, Bub1, BubR1, Mps1 and Mad2) releases a diffusible signal that inhibits the ubiquitin ligase activity of the anaphase promoting complex (APC) or cyclosome 6 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Cleveland, D. W., Mao, Y. & Sullivan, K. F. Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling. Cell 112, 407–421 (2003) source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlAPC/cyclosome function is required for sister chromatid separation and cytokinesis.
“APC/cyclosome function is required for sister chromatid separation and cytokinesis 7 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Yu, H. Regulation of APC-Cdc20 by the spindle checkpoint. Curr. Opin. Cell Biol. 14, 706–714 (2002) source
Not checked in the free run.
May combine two claims.
Interpretationreasoning§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlMad2 is overexpressed in several tumour types, where it correlates with high E2F activity and poor patient prognosis.
“Concordantly, Mad2 is overexpressed in several tumour types, where it correlates with high E2F activity and poor patient prognosis.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningAneuploidy is not necessarily a selected trait of cancer cells but can be an inadvertent consequence of defects that uncouple mitotic control from normal cell cycle progression.
“Our model also implies that aneuploidy is not necessarily a selected trait of cancer cells but can be an inadvertent consequence of defects that uncouple mitotic control from normal cell cycle progression.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenFISH signal counts were assessed in at least 200 interphase nuclei with strong and well-delineated contours.
“The number of hybridization signals for each probe was assessed in a minimum of 200 interphase nuclei with strong and well-delineated contours.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlMYCN overexpression and amplification can drive constitutive E2F activation.
“(which can drive E2F constitutive activation 21 )”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Schuldiner, O. & Benvenisty, N. A DNA microarray screen for genes involved in c-MYC and N-MYC oncogenesis in human tumors. Oncogene 20, 4984–4994 (2001) source
Not checked in the free run.
May combine two claims.
Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlRb pathway mutations promote tumour development by deregulating E2F transcription factors and causing uncontrolled cell cycle progression.
“These mutations promote tumour development by deregulating the E2F family of transcription factors leading to uncontrolled cell cycle progression 3 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Dyson, N. The regulation of E2F by pRB-family proteins. Genes Dev. 12, 2245–2262 (1998) source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOverexpression of securin produces aneuploidy and displays transforming activity in vivo and in vitro.
“overexpression of securin (Pds1, PTTG)-observed in many different tumour types-produces aneuploidy and displays transforming activity in vivo and in vitro 28 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Zou, H., McGarry, T. J., Bernal, T. & Kirschner, M. W. Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science 285, 418–422 (1999) source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic controlMAD2 clusters with tens of genes capable of predicting disease outcome in breast cancer patients.
“Interestingly, MAD2 also clusters with tens of genes capable of predicting disease outcome in breast cancer patients 22 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Van 't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002) source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningThe byproduct of Rb loss might subsequently increase the mutation rate, thereby fuelling further tumour evolution.
“Nevertheless, this byproduct of Rb loss might subsequently increase the mutation rate, thereby fuelling further tumour evolution.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningMutations disrupting Rb function produce deregulated E2F activity leading to inappropriate proliferation, aberrant Mad2 expression, and eventually aneuploidy.
“As a consequence, mutations that disrupt Rb function produce deregulated E2F activity leading to inappropriate proliferation, but also aberrant Mad2 expression and, eventually, aneuploidy.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The molecular defects causing aneuploidy and whether aneuploidy is a cause or a consequence of malignancy are unclear.
“However, the molecular defects underlying this trait, and whether they are a cause or a consequence of the malignant phenotype, are not clear.”
The paper relies on this without support.
E2F target genes are often constitutively expressed in cells with Rb pathway defects.
“E2F target genes are often constitutively expressed in cells with Rb pathway defects.”
The paper relies on this without support.
Retinoblastomas invariably lose Rb function and deregulate E2F.
“Retinoblastomas, which invariably lose Rb function and deregulate E2F, expressed high levels of Mad2 relative to normal retina”
The paper relies on this without support.
HCT116 is Rb-functional.
“Rb-functional T24 bladder carcinoma 17 and HCT116 colon carcinoma lines”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
RB-E2F complexes normally restrict expression of MAD2, a spindle checkpoint component.
“RB–E2F complexes are thought normally to restrict the expression of MAD2 (REF. 107), a spindle checkpoint component.”
From Cellular mechanisms of tumour suppression by the retinoblastoma gene (2008) · cites this paper as [107]
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“2a ), which deregulates endogenous E2F, and in cells where Rb was suppressed by stable RNA interference (RNAi) (shR”
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Flagged first, then by citations
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- Authors
- Hernando, E., Nahlé, Z., Juan, G., Diaz-Rodriguez, E., Alaminos, M., Hemann, M., Michel, L., Mittal, V., Gerald, W., Benezra, R., Lowe, S. W., & Cordon-Cardo, C.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Cold Spring Harbor Laboratory (US)
- Corresponding author
- Lowe, Scott W.
- ORCID
- Venue
- Nature
- Published
- 2004-08
- Volume
- 430
- Issue
- 7001
- Pages
- 797-802
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1984328656
- Semantic Scholar
- 141dd814c0253c79aab372f6397cd85a4797afd4
- Cited by
- 562
- References
- 25
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 13 · 2023: 25 · 2022: 14 · 2021: 13 · 2020: 8 · 2019: 19 · 2018: 13 · 2017: 14 · 2016: 17 · 2015: 31 · 2014: 19 · 2013: 19 · 2012: 43
- FWCI
- 17.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Gredos (University of Salamanca) (publishedVersion, cc-by-nc-nd)
- Hispana (publishedVersion, cc-by-nc-nd)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Department of Defense
- Howard Hughes Medical Institute
- Arthritis Foundation
- Memorial Sloan-Kettering Cancer Center
- Cold Spring Harbor Laboratory
- Ministerio de Educación, Cultura y Deporte
- National Cancer Institute (P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- retinoblastoma protein, Rb pathway, Mad2, E2F transcription factors, aneuploidy, chromosomal instability, spindle assembly checkpoint, cell cycle progression, mitosis, tumor progression, cancer prognosis
- MeSH terms
- Aneuploidy, Animals, Carrier Proteins, Cell Cycle, Cell Line, Chromosomes, Human, DNA-Binding Proteins, Humans, Immunohistochemistry, Karyotyping, Mitosis, Mutation, Nuclear Proteins, RNA, Messenger, Substrate Specificity, Transcription Factors, Signal Transduction, Gene Expression Regulation, Neoplastic, Retinoblastoma Protein, In Situ Hybridization, Fluorescence, Cell Cycle Proteins, Genomic Instability, Cell Line, Tumor, E2F Transcription Factors, Mice, Mad2 Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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