Chromosome segregation errors: a double-edged sword - TI Pharma

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Chapter 1 General Introduction Aniek Janssen 1,2, and René H. Medema 2 1 Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, the Netherlands 2 Division of Cell Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands Accepted in adapted form for publication in Oncogene 9 General Introduction 1
1 1. Introduction 1.1 The cell cycle Cell division, the generation of two new daughter cells from one mother cell, is an essential process for reproduction and development of organisms, but also for the maintenance and regeneration of vital tissues in the body. Eukaryotic cells, with the exception of germ cells, divide in a process called mitosis. Before two new daughter cells can be generated, mother cells need to have duplicated their DNA and essential organelles, processes which are being fulfilled in the phases preceding the mitotic phase. These phases are called the G1, S and G2 phase of the cell cycle, together termed interphase, and are sequentially initiated due to the activity of several Cyclin-dependent kinases (CDK) in complex with Cyclins, the main driving forces behind the cell cycle (reviewed in 1 ). The G1, or Gap1, phase ensures that a cell has obtained sufficient size and enough growth signals to enter the synthesis or S phase, in which the DNA gets duplicated during a process called replication. The following G2, or Gap2, phase has evolved to give the cell time to repair breaks in the newly synthesized DNA before it irreversibly enters mitosis. Mitosis in mammalian cells depends on the essential activity of Cyclin B1-Cdk1 and mitotic entry will only occur in the presence of sufficient activity of this major mitotic regulator (reviewed in 2 ). 1.2 Mitosis The DNA of the eukaryotic cell is orderly folded and packed into big structures called chromosomes, which are being kept close together in the nucleus of a cell. Each duplicated chromosome, or chromatid, remains associated with its sister chromatid from the moment of synthesis in S phase until the end of mitosis. This association is accomplished by the work of cohesins, multiprotein complexes that are thought to form a ring around the DNA strands of the two sisters 3 . The different mitotic phases together ensure the proper distribution of sister chromatids over the two daughter cells (Fig.1). Mitosis starts with breakdown of the nuclear envelope and condensation of the paired chromosomes in prophase. Subsequently, chromosomes need to congress to the cell’s equator (also known as the metaphase plate) in prometaphase, and remain there in metaphase until the sister chromatids can be separated to opposite sides of the cell in anaphase. Finally, to ensure full cell division, the process of cytokinesis separates the 10 Prophase Prometaphase Metaphase Anaphase Telophase Figure 1. Mitotic phases Mitosis starts with nuclear envelope breakdown and chromosome condensation in prophase. Bipolar spindle assembly is initiated when centrosomes move apart and start to nucleate microtubules. In prometaphase, the condensed sister chromatids each capture microtubules coming from opposite poles, which eventually leads to alignment of the chromosomes in between the two spindle poles during metaphase. Upon biorientation of all sister chromatids, anaphase is initiated and the cell’s cytoplasm is divided in two compartments upon cleavage furrow ingression in telophase. Representative time-lapse images are shown of a human osteosarcoma cell line stably expressing tubulin-RFP (red) and Histone-2B-GFP (green).
Page 2 and 3: Chromosome segregation errors: a do
Page 4 and 5: Chromosome segregation errors: a do
Page 6: Get up, stand up, stand up for your
Page 12 and 13: cytoplasms and pinches off the memb
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Page 24 and 25: that aberrant spindle formation inc
Page 26 and 27: (Fig.7C). As discussed in section 4
Page 28 and 29: Thesis outline Chromosome segregati
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Page 33 and 34: 2 Abstract Various types of chromos
Page 35 and 36: 2 34 A C D E % of cells Control 100
Page 37 and 38: 2 assess whether cytokinesis induce
Page 39 and 40: 2 A Asynchronous Monastrol release
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Page 43 and 44: 2 Immuno Blotting Cells were lysed
Page 45 and 46: 2 Supplemental figures 44 A B C % o
Page 47 and 48: 2 A MCF7 B C 53BP1 foci/cell 46 % o
Page 49 and 50: 2 A siLuc siATM C 48 p-S1981 ATM me
Page 51 and 52: 2 50 A B C % of EdU positive cells
Page 54 and 55: Chapter 3 Studying Chromosomal inst
Page 56 and 57: Introduction Aneuploidy is a common
Page 58 and 59: activity by ~80% 170-172 . With the
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A WT/CiMKi T649A Embryo’s: Figure
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control treated MEFs (unpaired t te
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Materials and Methods Cloning targe
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- Loop out BamHI site with site-dir
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Primers: pGH_pA_FW#2: TCTATGGCTTCTG
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was prepared using standard procedu
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71 Cre-inducible Mps1 knock-in mous
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4 Abstract Most of the current drug
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4 Two other interesting mitotic tar
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4 inhibition of the anti-apoptotic
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4 cluster their centrosomes. This
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4 of checkpoint function can be ach
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4 4.5 Disadvantages of exploiting m
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Chapter 5 Elevating the frequency o
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Introduction Error-free chromosome
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Partial depletion of Mps1 or BubR1
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death is not induced in the short t
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had survived growth for 7 days in t
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The following antibodies have been
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Supplemental data Supplemental figu
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A BubR1 α-tubulin Hela-TetRBubR1 -
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- doxycycline + doxycycline - doxyc
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A B C percentage of cells % PI posi
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Abstract One of the most common hal
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clear accumulation of cells in mito
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the mice did not receive any doxycy
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113 Chromosome missegregations kill
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Chapter 6 Aneuploid tumor cells are
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Introduction Equal segregation of t
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S1A, data not shown). Based on thes
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A B U2OS + H2B-YFP percentage of ce
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tumor cells, leaving diploid cells
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A B p-S10-Histone H3 DAPI C µmol/l
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Supplemental Figure-1. Protein bioc
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Bioavailability of compound-5 after
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A B U2OS (7.5nM) Hela (10nM) RPE-1
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7 Abstract Taxanes, such as docetax
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7 of mitotic aberrations. These dat
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7 A Low CFP lifetime High CFP lifet
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7 docetaxel treatment in vitro resu
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7 chromosome unstable, which means
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7 Cells (~50.000/well) were plated
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7 Supplemental data Supplemental fi
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7 148
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8 Thesis summary Unequal separation
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8 exerted through contraction of th
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8 1.4 NoCut: preventing the inducti
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8 tumorformation using intravital i
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Addendum References Nederlandse sam
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41. McEwen, B.F., et al., CENP-E is
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2010. 6(5): p. 359-68. 124. Liu, S.
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210. Stucki, M., et al., MDC1 direc
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tumors in mice. Cancer Res, 2007. 6
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adiotherapy in breast cancer. Breas
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470. Marcus, A.I., et al., Mitotic
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559. Kienitz, A., et al., Partial d
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Nederlandse Samenvatting Celdeling,
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verdeling van tumorcellen compleet
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Publications A. Janssen, R.H.Medema
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En dan zijn er nu nog een aantal li
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promotie-stukjes! Je bent een voorb
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edankt voor al jullie hulp bij de i
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Chromosome segregation errors: a double-edged sword - TI Pharma

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