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Autochthonous tumors driven by loss have an ongoing requirement for the RBP2 histone demethylase.
McBrayer SK, Olenchock BA, DiNatale GJ, Shi DD, Khanal J, Jennings RB, Novak JS, Oser MG, Robbins AK, Modiste R, Bonal D, Moslehi J, Bronson RT, Neuberg D, Nguyen QD, Signoretti S, Losman JA, Kaelin WG
(2018) Proc Natl Acad Sci U S A 115: E3741-E3748
MeSH Terms: Alleles, Animals, DNA-Binding Proteins, Echocardiography, Enzyme Activation, Fibroblasts, Genes, Retinoblastoma, Heart Septal Defects, Histone Code, Integrases, Jumonji Domain-Containing Histone Demethylases, Mice, Mice, Inbred C57BL, Molecular Targeted Therapy, Neoplasm Proteins, Pituitary Neoplasms, Recombinant Fusion Proteins, Retinoblastoma Protein, Tamoxifen, Thyroid Neoplasms, Transgenes
Show Abstract · Added April 22, 2018
Inactivation of the retinoblastoma gene () product, pRB, is common in many human cancers. Targeting downstream effectors of pRB that are central to tumorigenesis is a promising strategy to block the growth of tumors harboring loss-of-function mutations. One such effector is retinoblastoma-binding protein 2 (RBP2, also called JARID1A or KDM5A), which encodes an H3K4 demethylase. Binding of pRB to RBP2 has been linked to the ability of pRB to promote senescence and differentiation. Importantly, genetic ablation of RBP2 is sufficient to phenocopy pRB's ability to induce these cellular changes in cell culture experiments. Moreover, germline deletion significantly impedes tumorigenesis in mice. The value of RBP2 as a therapeutic target in cancer, however, hinges on whether loss of RBP2 could block the growth of established tumors as opposed to simply delaying their onset. Here we show that conditional, systemic ablation of RBP2 in tumor-bearing mice is sufficient to slow tumor growth and significantly extend survival without causing obvious toxicity to the host. These findings show that established -null tumors require RBP2 for growth and further credential RBP2 as a therapeutic target in human cancers driven by inactivation.
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21 MeSH Terms
Comprehensive genomic profiles of small cell lung cancer.
George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G, Leenders F, Lu X, Fernández-Cuesta L, Bosco G, Müller C, Dahmen I, Jahchan NS, Park KS, Yang D, Karnezis AN, Vaka D, Torres A, Wang MS, Korbel JO, Menon R, Chun SM, Kim D, Wilkerson M, Hayes N, Engelmann D, Pützer B, Bos M, Michels S, Vlasic I, Seidel D, Pinther B, Schaub P, Becker C, Altmüller J, Yokota J, Kohno T, Iwakawa R, Tsuta K, Noguchi M, Muley T, Hoffmann H, Schnabel PA, Petersen I, Chen Y, Soltermann A, Tischler V, Choi CM, Kim YH, Massion PP, Zou Y, Jovanovic D, Kontic M, Wright GM, Russell PA, Solomon B, Koch I, Lindner M, Muscarella LA, la Torre A, Field JK, Jakopovic M, Knezevic J, Castaños-Vélez E, Roz L, Pastorino U, Brustugun OT, Lund-Iversen M, Thunnissen E, Köhler J, Schuler M, Botling J, Sandelin M, Sanchez-Cespedes M, Salvesen HB, Achter V, Lang U, Bogus M, Schneider PM, Zander T, Ansén S, Hallek M, Wolf J, Vingron M, Yatabe Y, Travis WD, Nürnberg P, Reinhardt C, Perner S, Heukamp L, Büttner R, Haas SA, Brambilla E, Peifer M, Sage J, Thomas RK
(2015) Nature 524: 47-53
MeSH Terms: Alleles, Animals, Cell Line, Tumor, Chromosome Breakpoints, Cyclin D1, DNA-Binding Proteins, Disease Models, Animal, Female, Gene Expression Profiling, Genome, Human, Genomics, Humans, Lung Neoplasms, Male, Mice, Mutation, Neurosecretory Systems, Nuclear Proteins, Receptors, Notch, Retinoblastoma Protein, Signal Transduction, Small Cell Lung Carcinoma, Tumor Protein p73, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
Show Abstract · Added February 16, 2016
We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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25 MeSH Terms
Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway.
Zhang B, Zhang B, Chen X, Bae S, Singh K, Washington MK, Datta PK
(2014) Br J Cancer 110: 946-57
MeSH Terms: Animals, Antimetabolites, Antineoplastic, Cell Cycle Proteins, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Survival, Chromones, Colorectal Neoplasms, Drug Resistance, Neoplasm, Enzyme Activation, Enzyme Inhibitors, Fluorouracil, Humans, Inhibitor of Apoptosis Proteins, Mice, Mice, Inbred BALB C, Morpholines, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Transplantation, Neovascularization, Pathologic, Phosphatidylinositol 3-Kinase, Phosphatidylinositol 3-Kinases, Phosphorylation, Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Repressor Proteins, Retinoblastoma Protein, Smad4 Protein, Survivin, Up-Regulation, Vascular Endothelial Growth Factor A, Wound Healing, Xenograft Model Antitumor Assays
Show Abstract · Added April 12, 2016
BACKGROUND - Higher frequency of Smad4 inactivation or loss of expression is observed in metastasis of colorectal cancer (CRC) leading to unfavourable survival and contributes to chemoresistance. However, the molecular mechanism of how Smad4 regulates chemosensitivity of CRC is unknown.
METHODS - We evaluated how the loss of Smad4 in CRC enhanced chemoresistance to 5-fluorouracil (5-FU) using two CRC cell lines in vitro and in vivo. Immunoblotting with cell and tumour lysates and immunohistochemical analyses with tissue microarray were performed.
RESULTS - Knockdown or loss of Smad4 induced tumorigenicity, migration, invasion, angiogenesis, metastasis, and 5-FU resistance. Smad4 expression in mouse tumours regulated cell-cycle regulatory proteins leading to Rb phosphorylation. Loss of Smad4 activated Akt pathway that resulted in upregulation of anti-apoptotic proteins, Bcl-2 and Bcl-w, and Survivin. Suppression of phosphatidylinositol-3-kinase (PI3K)/Akt pathway by LY294002 restored chemosensitivity of Smad4-deficient cells to 5-FU. Vascular endothelial growth factor-induced angiogenesis in Smad4-deficient cells might also lead to chemoresistance. Low levels of Smad4 expression in CRC tissues correlated with higher levels of Bcl-2 and Bcl-w and with poor overall survival as observed in immunohistochemical staining of tissue microarrays.
CONCLUSION - Loss of Smad4 in CRC patients induces resistance to 5-FU-based therapy through activation of Akt pathway and inhibitors of this pathway may sensitise these patients to 5-FU.
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36 MeSH Terms
Comprehensive molecular portraits of human breast tumours.
Cancer Genome Atlas Network
(2012) Nature 490: 61-70
MeSH Terms: Breast Neoplasms, Class I Phosphatidylinositol 3-Kinases, DNA Copy Number Variations, DNA Methylation, DNA Mutational Analysis, Exome, Female, GATA3 Transcription Factor, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, BRCA1, Genes, Neoplasm, Genes, erbB-2, Genes, p53, Genetic Heterogeneity, Genome, Human, Genomics, Humans, MAP Kinase Kinase Kinase 1, MicroRNAs, Mutation, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Phosphatidylinositol 3-Kinases, Protein Array Analysis, Proteomics, RNA, Messenger, RNA, Neoplasm, Receptors, Estrogen, Retinoblastoma Protein
Show Abstract · Added March 28, 2014
We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.
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30 MeSH Terms
Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer.
Peifer M, Fernández-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, Plenker D, Leenders F, Sun R, Zander T, Menon R, Koker M, Dahmen I, Müller C, Di Cerbo V, Schildhaus HU, Altmüller J, Baessmann I, Becker C, de Wilde B, Vandesompele J, Böhm D, Ansén S, Gabler F, Wilkening I, Heynck S, Heuckmann JM, Lu X, Carter SL, Cibulskis K, Banerji S, Getz G, Park KS, Rauh D, Grütter C, Fischer M, Pasqualucci L, Wright G, Wainer Z, Russell P, Petersen I, Chen Y, Stoelben E, Ludwig C, Schnabel P, Hoffmann H, Muley T, Brockmann M, Engel-Riedel W, Muscarella LA, Fazio VM, Groen H, Timens W, Sietsma H, Thunnissen E, Smit E, Heideman DA, Snijders PJ, Cappuzzo F, Ligorio C, Damiani S, Field J, Solberg S, Brustugun OT, Lund-Iversen M, Sänger J, Clement JH, Soltermann A, Moch H, Weder W, Solomon B, Soria JC, Validire P, Besse B, Brambilla E, Brambilla C, Lantuejoul S, Lorimier P, Schneider PM, Hallek M, Pao W, Meyerson M, Sage J, Shendure J, Schneider R, Büttner R, Wolf J, Nürnberg P, Perner S, Heukamp LC, Brindle PK, Haas S, Thomas RK
(2012) Nat Genet 44: 1104-10
MeSH Terms: Amino Acid Substitution, Animals, CREB-Binding Protein, Cell Line, Tumor, DNA Copy Number Variations, DNA Mutational Analysis, E1A-Associated p300 Protein, Gene Expression Profiling, Gene Regulatory Networks, Genome, Human, Genome-Wide Association Study, Histone-Lysine N-Methyltransferase, Humans, Intercellular Signaling Peptides and Proteins, Lung Neoplasms, Mice, Mice, Knockout, Models, Molecular, Mutation, Myeloid-Lymphoid Leukemia Protein, Nerve Tissue Proteins, Oligonucleotide Array Sequence Analysis, PTEN Phosphohydrolase, Polymorphism, Single Nucleotide, Protein Processing, Post-Translational, Retinoblastoma Protein, Small Cell Lung Carcinoma, Tumor Suppressor Protein p53
Show Abstract · Added September 3, 2013
Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis. We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4±1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.
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28 MeSH Terms
Binding to retinoblastoma pocket domain does not alter the inter-domain flexibility of the J domain of SV40 large T antigen.
Williams CK, Vaithiyalingam S, Hammel M, Pipas J, Chazin WJ
(2012) Arch Biochem Biophys 518: 111-8
MeSH Terms: Amino Acid Motifs, Antigens, Polyomavirus Transforming, Multiprotein Complexes, Nuclear Magnetic Resonance, Biomolecular, Protein Binding, Protein Structure, Quaternary, Protein Structure, Tertiary, Retinoblastoma Protein
Show Abstract · Added March 7, 2014
Simian Virus 40 uses the large T antigen (Tag) to bind and inactivate retinoblastoma tumor suppressor proteins (Rb), which can result in cellular transformation. Tag is a modular protein with four domains connected by flexible linkers. The N-terminal J domain of Tag is necessary for Rb inactivation. Binding of Rb is mediated by an LXCXE consensus motif immediately C-terminal to the J domain. Nuclear magnetic resonance (NMR) and small angle X-ray scattering (SAXS) were used to study the structural dynamics and interaction of Rb with the LXCXE motif, the J domain and a construct (N(260)) extending from the J domain through the origin binding domain (OBD). NMR and SAXS data revealed substantial flexibility between the domains in N(260). Binding of pRb to a construct containing the LXCXE motif and the J domain revealed weak interactions between pRb and the J domain. Analysis of the complex of pRb and N(260) indicated that the OBD is not involved and retains its dynamic independence from the remainder of Tag. These results support a 'chaperone' model in which the J domain of Tag changes its orientation as it acts upon different protein complexes.
Copyright © 2011 Elsevier Inc. All rights reserved.
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8 MeSH Terms
E2f binding-deficient Rb1 protein suppresses prostate tumor progression in vivo.
Sun H, Wang Y, Chinnam M, Zhang X, Hayward SW, Foster BA, Nikitin AY, Wills M, Goodrich DW
(2011) Proc Natl Acad Sci U S A 108: 704-9
MeSH Terms: Alleles, Animals, DNA Mutational Analysis, Disease Models, Animal, Disease Progression, E2F Transcription Factors, Genes, Retinoblastoma, Heterozygote, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Prostatic Neoplasms, Retinoblastoma Protein
Show Abstract · Added May 27, 2014
Mutational inactivation of the RB1 tumor suppressor gene initiates retinoblastoma and other human cancers. RB1 protein (pRb) restrains cell proliferation by binding E2f transcription factors and repressing the expression of cell cycle target genes. It is presumed that loss of pRb/E2f interaction accounts for tumor initiation, but this has not been directly tested. RB1 mutation is a late event in other human cancers, suggesting a role in tumor progression as well as initiation. It is currently unknown whether RB1 mutation drives tumor progression and, if so, whether loss of pRb/E2f interaction is responsible. We have characterized tumorigenesis in mice expressing a mutant pRb that is specifically deficient in binding E2f. In endocrine tissue, the mutant pRb has no detectable effect on tumorigenesis. In contrast, it significantly delays progression to invasive and lethal prostate cancer. Tumor delay is associated with induction of a senescence response. We conclude that the pRb/E2f interaction is critical for preventing tumor initiation, but that pRb can use additional context-dependent mechanisms to restrain tumor progression.
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15 MeSH Terms
NRMT is an alpha-N-methyltransferase that methylates RCC1 and retinoblastoma protein.
Tooley CE, Petkowski JJ, Muratore-Schroeder TL, Balsbaugh JL, Shabanowitz J, Sabat M, Minor W, Hunt DF, Macara IG
(2010) Nature 466: 1125-8
MeSH Terms: Cell Cycle Proteins, Cell Line, Chromosome Segregation, Gene Knockdown Techniques, Guanine Nucleotide Exchange Factors, HeLa Cells, Histone Chaperones, Humans, Methyltransferases, Models, Molecular, Mutation, Nuclear Proteins, Protein Binding, Protein Structure, Tertiary, Retinoblastoma Protein, Spindle Apparatus, Transcription Factors
Show Abstract · Added March 5, 2014
The post-translational methylation of alpha-amino groups was first discovered over 30 years ago on the bacterial ribosomal proteins L16 and L33 (refs 1, 2), but almost nothing is known about the function or enzymology of this modification. Several other bacterial and eukaryotic proteins have since been shown to be alpha-N-methylated. However, the Ran guanine nucleotide-exchange factor, RCC1, is the only protein for which any biological function of alpha-N-methylation has been identified. Methylation-defective mutants of RCC1 have reduced affinity for DNA and cause mitotic defects, but further characterization of this modification has been hindered by ignorance of the responsible methyltransferase. All fungal and animal N-terminally methylated proteins contain a unique N-terminal motif, Met-(Ala/Pro/Ser)-Pro-Lys, indicating that they may be targets of the same, unknown enzyme. The initiating Met is cleaved, and the exposed alpha-amino group is mono-, di- or trimethylated. Here we report the discovery of the first alpha-N-methyltransferase, which we named N-terminal RCC1 methyltransferase (NRMT). Substrate docking and mutational analysis of RCC1 defined the NRMT recognition sequence and enabled the identification of numerous new methylation targets, including SET (also known as TAF-I or PHAPII) and the retinoblastoma protein, RB. Knockdown of NRMT recapitulates the multi-spindle phenotype seen with methylation-defective RCC1 mutants, demonstrating the importance of alpha-N-methylation for normal bipolar spindle formation and chromosome segregation.
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17 MeSH Terms
Down-regulation of p57Kip2 induces prostate cancer in the mouse.
Jin RJ, Lho Y, Wang Y, Ao M, Revelo MP, Hayward SW, Wills ML, Logan SK, Zhang P, Matusik RJ
(2008) Cancer Res 68: 3601-8
MeSH Terms: Animals, Cell Differentiation, Cell Line, Tumor, Cell Transformation, Neoplastic, Cyclin D, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase Inhibitor p57, Cyclins, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Prostatic Neoplasms, Retinoblastoma Protein
Show Abstract · Added December 10, 2013
p57(Kip2) has been considered a candidate tumor suppressor gene because of its location in the genome, biochemical activities, and imprinting status. However, little is known about the role of p57(Kip2) in tumorigenesis and cancer progression. Here, we show that the expression of p57(Kip2) is significantly decreased in human prostate cancer, and the overexpression of p57(Kip2) in prostate cancer cells significantly suppressed cell proliferation and reduced invasive ability. In addition, overexpression of p57(Kip2) in LNCaP cells inhibited tumor formation in nude mice, resulting in well-differentiated squamous tumors rather than adenocarcinoma. Furthermore, the prostates of p57(Kip2) knockout mice developed prostatic intraepithelial neoplasia and adenocarcinoma. Remarkably, this mouse prostate cancer is pathologically identical to human prostate adenocarcinoma. Therefore, these results strongly suggest that p57(Kip2) is an important gene in prostate cancer tumorigenesis, and the p57(Kip2) pathway may be a potential target for prostate cancer prevention and therapy.
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16 MeSH Terms
CMF1-Rb interaction promotes myogenesis in avian skeletal myoblasts.
Robertson JB, Zhu T, Nasreen S, Kilkenny D, Bader D, Dees E
(2008) Dev Dyn 237: 1424-33
MeSH Terms: Animals, Cell Cycle, Cell Differentiation, Cell Line, Cell Proliferation, Chromosomal Proteins, Non-Histone, Contractile Proteins, Humans, Mice, Microfilament Proteins, Muscle Development, Muscle Proteins, Muscle, Skeletal, MyoD Protein, Myoblasts, Myocytes, Cardiac, Myogenic Regulatory Factor 5, Myogenin, Protein Binding, Quail, Retinoblastoma Protein
Show Abstract · Added May 29, 2014
CMF1 protein is expressed in developing striated muscle before the expression of contractile proteins, and depletion of CMF1 in myoblasts results in inability to express muscle-specific proteins. Previous studies of CMF1 identify a functional Rb-binding domain, which is conserved in the murine and human homologues. Here, we show that CMF1 binds Rb family members, while a CMF1 protein with deletion of the Rb-binding domain (Rb-del CMF1) does not. Myogenic cell lines over-expressing Rb-del CMF1 proliferate normally, but exhibit markedly impaired differentiation, including dramatically reduced contractile proteins gene expression and failure to fuse into myotubes. Furthermore, by quantitative real-time polymerase chain reaction, MyoD and Myf5 mRNA levels are comparable to wild-type, while myogenin and contractile protein mRNA levels are significantly attenuated. These data demonstrate that CMF1 regulates myocyte differentiation by interaction with Rb family members to induce expression of myogenic regulatory factors.
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21 MeSH Terms