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  • 1
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    Control of chromosome stability by the beta-TrCP-REST-Mad2 axis (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-03-21
    Description: REST/NRSF (repressor-element-1-silencing transcription factor/neuron-restrictive silencing factor) negatively regulates the transcription of genes containing RE1 sites. REST is expressed in non-neuronal cells and stem/progenitor neuronal cells, in which it inhibits the expression of neuron-specific genes. Overexpression of REST is frequently found in human medulloblastomas and neuroblastomas, in which it is thought to maintain the stem character of tumour cells. Neural stem cells forced to express REST and c-Myc fail to differentiate and give rise to tumours in the mouse cerebellum. Expression of a splice variant of REST that lacks the carboxy terminus has been associated with neuronal tumours and small-cell lung carcinomas, and a frameshift mutant (REST-FS), which is also truncated at the C terminus, has oncogenic properties. Here we show, by using an unbiased screen, that REST is an interactor of the F-box protein beta-TrCP. REST is degraded by means of the ubiquitin ligase SCF(beta-TrCP) during the G2 phase of the cell cycle to allow transcriptional derepression of Mad2, an essential component of the spindle assembly checkpoint. The expression in cultured cells of a stable REST mutant, which is unable to bind beta-TrCP, inhibited Mad2 expression and resulted in a phenotype analogous to that observed in Mad2(+/-) cells. In particular, we observed defects that were consistent with faulty activation of the spindle checkpoint, such as shortened mitosis, premature sister-chromatid separation, chromosome bridges and mis-segregation in anaphase, tetraploidy, and faster mitotic slippage in the presence of a spindle inhibitor. An indistinguishable phenotype was observed by expressing the oncogenic REST-FS mutant, which does not bind beta-TrCP. Thus, SCF(beta-TrCP)-dependent degradation of REST during G2 permits the optimal activation of the spindle checkpoint, and consequently it is required for the fidelity of mitosis. The high levels of REST or its truncated variants found in certain human tumours may contribute to cellular transformation by promoting genomic instability.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707768/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707768/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guardavaccaro, Daniele -- Frescas, David -- Dorrello, N Valerio -- Peschiaroli, Angelo -- Multani, Asha S -- Cardozo, Timothy -- Lasorella, Anna -- Iavarone, Antonio -- Chang, Sandy -- Hernando, Eva -- Pagano, Michele -- R01 GM057587/GM/NIGMS NIH HHS/ -- R01 GM057587-10/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Mar 20;452(7185):365-9. doi: 10.1038/nature06641.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, MSB 599, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18354482" target="_blank"〉PubMed〈/a〉
    Keywords: Calcium-Binding Proteins/genetics/*metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line ; *Chromosomal Instability ; G2 Phase ; Gene Expression Regulation ; Genomic Instability ; Humans ; Mad2 Proteins ; Mitosis ; Protein Binding ; Repressor Proteins/genetics/*metabolism ; SKP Cullin F-Box Protein Ligases/metabolism ; Spindle Apparatus/physiology ; Transcription Factors/genetics/*metabolism ; beta-Transducin Repeat-Containing Proteins/deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    An ID2-dependent mechanism for VHL inactivation in cancer (2016)
    Nature Publishing Group (NPG)
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    Publication Date: 2016-01-07
    Description: Mechanisms that maintain cancer stem cells are crucial to tumour progression. The ID2 protein supports cancer hallmarks including the cancer stem cell state. HIFalpha transcription factors, most notably HIF2alpha (also known as EPAS1), are expressed in and required for maintenance of cancer stem cells (CSCs). However, the pathways that are engaged by ID2 or drive HIF2alpha accumulation in CSCs have remained unclear. Here we report that DYRK1A and DYRK1B kinases phosphorylate ID2 on threonine 27 (Thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (also known as EGLN2). ID2 binds to the VHL ubiquitin ligase complex, displaces VHL-associated Cullin 2, and impairs HIF2alpha ubiquitylation and degradation. Phosphorylation of Thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2alpha ubiquitylation. In glioblastoma, ID2 positively modulates HIF2alpha activity. Conversely, elevated expression of DYRK1 phosphorylates Thr27 of ID2, leading to HIF2alpha destabilization, loss of glioma stemness, inhibition of tumour growth, and a more favourable outcome for patients with glioblastoma.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Sang Bae -- Frattini, Veronique -- Bansal, Mukesh -- Castano, Angelica M -- Sherman, Dan -- Hutchinson, Keino -- Bruce, Jeffrey N -- Califano, Andrea -- Liu, Guangchao -- Cardozo, Timothy -- Iavarone, Antonio -- Lasorella, Anna -- R01CA101644/CA/NCI NIH HHS/ -- R01CA131126/CA/NCI NIH HHS/ -- R01CA178546/CA/NCI NIH HHS/ -- R01NS061776/NS/NINDS NIH HHS/ -- England -- Nature. 2016 Jan 14;529(7585):172-7. doi: 10.1038/nature16475. Epub 2016 Jan 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cancer Genetics, Columbia University Medical Center, New York 10032, USA. ; Department of Systems Biology, Columbia University Medical Center, New York 10032, USA. ; Center for Computational Biology and Bioinformatics, Columbia University Medical Center, New York 10032, USA. ; Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York 10014, USA. ; Department of Neurosurgery, Columbia University Medical Center, New York 10032, USA. ; Department of Neurology, Columbia University Medical Center, New York 10032, USA. ; Department of Pathology, Columbia University Medical Center, New York 10032, USA. ; Department of Pediatrics, Columbia University Medical Center, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26735018" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cell Hypoxia ; Cell Line, Tumor ; Cullin Proteins/metabolism ; Glioblastoma/*metabolism/*pathology ; Humans ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism ; Inhibitor of Differentiation Protein 2/*metabolism ; Male ; Mice ; Neoplastic Stem Cells/*metabolism/pathology ; Oxygen/metabolism ; Phosphorylation ; Phosphothreonine/metabolism ; Protein Binding ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Protein-Tyrosine Kinases/antagonists & inhibitors/metabolism ; Ubiquitination ; Von Hippel-Lindau Tumor Suppressor Protein/*antagonists & inhibitors/metabolism ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Aldolase provides an unusual binding site for thrombospondin-related anonymous protein in the invasion machinery of the malaria parasite (2007)
    National Academy of Sciences
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    Publication Date: 2007-04-10
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    New class of molecules predicted to exhibit non-linear optical properties (2005)
    Springer
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    Publication Date: 2005-07-01
    Print ISSN: 0022-2461
    Electronic ISSN: 1573-4803
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Published by Springer
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  • 5
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    An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway (2011)
    National Academy of Sciences
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    Publication Date: 2011-03-10
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 6
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    An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway [Cell Biology] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-04-13
    Description: Misregulated β-catenin responsive transcription (CRT) has been implicated in the genesis of various malignancies, including colorectal carcinomas, and it is a key therapeutic target in combating various cancers. Despite significant effort, successful clinical implementation of CRT inhibitory therapeutics remains a challenging goal. This is, in part, because of the challenge of identifying inhibitory compounds that specifically modulate the nuclear transcriptional activity of β-catenin while not affecting its cytoskeletal function in stabilizing adherens junctions at the cell membrane. Here, we report an RNAi-based modifier screening strategy for the identification of CRT inhibitors. Our data provide support for the specificity of these inhibitory compounds in antagonizing the transcriptional function of nuclear β-catenin. We show that these inhibitors efficiently block Wnt/β-catenin–induced target genes and phenotypes in various mammalian and cancer cell lines. Importantly, these Wnt inhibitors are specifically cytotoxic to human colon tumor biopsy cultures as well as colon cancer cell lines that exhibit deregulated Wnt signaling.
    Keywords: Feature Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 7
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    Visualizing the phage T4 activated transcription complex of DNA and E. coli RNA polymerase (2016)
    Oxford University Press
    Details
    Publication Date: 2016-09-20
    Description: The ability of RNA polymerase (RNAP) to select the right promoter sequence at the right time is fundamental to the control of gene expression in all organisms. However, there is only one crystallized structure of a complete activator/RNAP/DNA complex. In a process called appropriation, bacteriophage T4 activates a class of phage promoters using an activator (MotA) and a co-activator (AsiA), which function through interactions with the 70 subunit of RNAP. We have developed a holistic, structure-based model for appropriation using multiple experimentally determined 3D structures ( Escherichia coli RNAP, the Thermus aquaticus RNAP/DNA complex, AsiA / 70 Region 4, the N-terminal domain of MotA [MotA NTD ], and the C-terminal domain of MotA [MotA CTD ]), molecular modeling, and extensive biochemical observations indicating the position of the proteins relative to each other and to the DNA. Our results visualize how AsiA/MotA redirects , and therefore RNAP activity, to T4 promoter DNA, and demonstrate at a molecular level how the tactful interaction of transcriptional factors with even small segments of RNAP can alter promoter specificity. Furthermore, our model provides a rational basis for understanding how a mutation within the β subunit of RNAP (G1249D), which is far removed from AsiA or MotA, impairs appropriation.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    Density Functional Computations and Molecular Dynamics Simulations of the Triethylammonium Triflate Protic Ionic Liquid (2017)
    American Chemical Society (ACS)
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    Publication Date: 2017-12-13
    Description: The Journal of Physical Chemistry B DOI: 10.1021/acs.jpcb.7b10373
    Electronic ISSN: 1520-5207
    Topics: Chemistry and Pharmacology , Physics
    Published by American Chemical Society (ACS)
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