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cell cycle regulation - Ebook USA ( biotechnology)
Results and Problems in Cell Differentiation 42 Series Editors D Richter, H Tiedge Philipp Kaldis (Ed.) Cell Cycle Regulation With 26 Figures, in Color, and Tables 123 Philipp Kaldis, PhD National Cancer Institute, NCI-Frederick 1050 Boyles Street Bldg 560 Frederick, MD 21702-1201 USA ISSN 0080-1844 ISBN-10 3-540-34552-3 Springer Berlin Heidelberg New York ISBN-13 978-3-540-34552-7 Springer Berlin Heidelberg New York Library of Congress Control Number: 2006925965 This work is subject to copyright All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer Violations are liable for prosecution under the German Copyright Law Springer is a part of Springer Science+Business Media springer.com c Springer-Verlag Berlin Heidelberg 2006 Printed in Germany The use of registered names, trademarks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use Cover design: Design & Production GmbH, Heidelberg Typesetting and Production: LE-TEX Jelonek, Schmidt & Vöckler GbR, Leipzig Printed on acid-free paper 31/3150/YL – Preface The cell cycle is tightly regulated on many different levels to ensure properly controlled proliferation In the last 20 years, through the contributions of many laboratories, we have gained insight into many important aspects of the regulation of the cell cycle and its relation to cancer, which culminated in the 2001 Nobel Prize being awarded to Leland Hartwell, Tim Hunt, and Paul Nurse In the investigations of cell cycle regulation, it has been essential to use different model systems from yeast to mouse, where the results from one system have led to advances in another system Recently, studies have been done using more complex organisms like the mouse, which has taught us much about redundancy and flexibility in the regulation of the cell cycle Some of the (even fundamental) results from yeast or mammalian cell lines had to be revised since they were not completely applicable to complex animal systems It is a major challenge to keep an open mind when new results overthrow established dogmas, especially since some of the dogmas have never been backed by convincing experiments This book will provide an updated view of some of the most exciting areas of cell cycle regulation The chapters of this book have been written by experts in the cell cycle field and cover topics ranging from yeast to mouse and from Rb to sterility In the first chapter Moeller and Sheaff review recent results regarding G1 phase control, which might suggest that depending on the context or cell type, the G1 phase control could be different The second chapter by Teer and Dutta deals with the regulation of DNA replication during the S phase They discuss the origin of replication complex, MCMs, and how they are controlled by different factors The next chapter, by Yang and Zou, reviews checkpoints and the response to DNA damage, followed by a chapter by Hoffmann, which deals with protein kinases that are involved in the regulation of the mitotic spindle checkpoint The regulation of the centrosome cycle is discussed in the chapter by Mattison and Winey In the sixth chapter Reed reviews the regulation of the cell cycle by ubiquitin-mediated degradation The next chapter, by Dannenberg and Te Riele, deals with the Rb family and its control of the cell cycle using in vivo systems Lili Yamasaki reviews the relations between cancer and the Rb/E2F pathway in the eighth chapter and Hiroaki Kiyokawa then discusses interactions of senescence and cell cycle control Aleem and Kaldis follow with new concepts obtained by studying mouse models of cell cycle regulators In VI Preface the eleventh chapter Bernard and Eilers review the functions of Myc in the control of cell growth and proliferation The book concludes with a chapter by Rajesh and Pittman, who discuss the relations of cell cycle regulators and mammalian germ cells The future challenges in cell cycle research will be to integrate our knowledge coming from different systems, extend it to tumorigenesis in humans, and use all this information to design clinically relevant studies This cannot happen in one step or overnight and will necessitate a lot of effort It will continue to require broad-based basic research, along with the development of relevant animal models These animal models need to recapitulate human diseases as closely as possible Currently, many questions remain regarding animals being good models for human diseases Nevertheless, more effort needs to be expended in developing better animal models before conclusions can be drawn It is obvious that without appropriate animal models we will have to continue to test newly developed drugs in clinical trials without knowing the potential outcome This is a time-consuming and risky procedure, which has been going on for too long a time The future of cell cycle research is bright and the results of such studies will hopefully influence the battle against cancer This book could not have been completed without the outstanding contributions from the authors and I would like to thank them all for their valuable effort In addition, I thank the members of the Kaldis lab as well as Michele Pagano for encouragement and support I also acknowledge the support of Ursula Gramm, Sabine Schreck (Springer, Heidelberg), and Michael Reinfarth (Le-TeX GbR, Leipzig) for editorial managing and production of this book March 2006 Philipp Kaldis Contents G1 Phase: Components, Conundrums, Context Stephanie J Moeller, Robert J Sheaff Introduction Arrival of the Cycle 2.1 Discrete Events during Division 2.2 Maintaining Order 2.3 Cell Cycle Machinery G1 Progression in Cultured Cells 3.1 Coordinating Cell Growth and Division 3.2 Information Integration 3.3 The Cyclin-Cdk Engine 3.4 Removing Impediments: Inactivating Rb 3.5 Removing Impediments: Inactivating p27kip1 3.6 Preparing for the Future Ablating G1 Regulators in Mice 4.1 Cyclin D-Cdk4/6 4.2 Cyclin E/Cdk2 4.3 G1 Targets Implications and Future Directions 5.1 Conundrums 5.2 G1 in Context Conclusions References 1 2 10 11 12 12 14 16 19 19 20 23 24 Regulation of S Phase Jamie K Teer, Anindya Dutta Introduction Origins of Replication 2.1 Genome Replicator Sequences Pre-Replication Complex 3.1 ORC 3.2 Cdt1 3.3 Cdc6 31 31 32 32 35 35 37 38 VIII 3.4 MCM2-7 3.5 Geminin 3.6 Summary Pre-Initiation Complex 4.1 Mcm10 4.2 Cdc45 4.3 Dbf4/Cdc7 4.4 GINS 4.5 DPB11 4.6 Summary S-phase Regulation and Cancer Conclusion References Contents 40 41 42 43 43 44 45 46 47 47 49 50 52 65 65 66 66 69 71 73 74 76 77 78 79 80 81 82 83 Protein Kinases Involved in Mitotic Spindle Checkpoint Regulation Ingrid Hoffmann Introduction The Spindle Assembly Checkpoint Regulation of the Spindle Checkpoint by Protein Kinases 3.1 Bub1 3.2 BubR1 3.3 Aurora B 3.4 Mps1 3.5 Mitogen-activated protein kinase The Spindle Checkpoint and Cancer 93 93 94 95 95 98 99 101 102 102 Checkpoint and Coordinated Cellular Responses to DNA Damage Xiaohong H Yang, Lee Zou Introduction Sensing DNA Damage and DNA Replication Stress 2.1 Recruitment of ATR to DNA 2.2 DNA Damage Recognition by the RFC- and PCNA-like Checkpoint Complexes 2.3 Processing of DNA Lesions 2.4 MRN Complex and Activation of ATM and ATR Transduction of DNA Damage Signals Regulation of Downstream Cellular Processes 4.1 Regulation of the Cell Cycle 4.2 Regulation of DNA Replication Forks 4.3 Regulation of DNA Repair 4.4 Regulation of Telomeres Interplay between Checkpoint Signaling and Chromatin Perspectives References Contents IX Conclusions 104 References 104 The Centrosome Cycle Christopher P Mattison, Mark Winey Introduction 1.1 History 1.2 Microtubule Organizing Centers 1.3 Centrosome Functions 1.4 Centrosome Dysfunction and Cancer/Disease 1.5 Centrosome Structure The Centrosome Cycle 2.1 Introduction 2.2 Centrosome Duplication 2.3 Centrosome Maturation 2.4 Centrosome Separation 2.5 Licensing of Centrosome Duplication 2.6 Post-Mitosis Return to G1 Conclusion References 111 111 111 112 112 113 113 114 114 116 126 130 133 133 134 135 The Ubiquitin-Proteasome Pathway in Cell Cycle Control Steven I Reed Introduction The Ubiquitin-Proteasome Pathway Protein-Ubiquitin Ligases in the Cell Cycle Core Machinery 3.1 APC/C Protein-Ubiquitin Ligases 3.2 APC/C Substrates and Biology 3.3 APC/C and Meiosis 3.4 SCF Protein-Ubiquitin Ligases 3.5 SCF Substrates and Biology 3.6 Regulation of SCF Activity Checkpoint Control Atypical Roles of Proteasomes and Ubiquitylation Deubiquitylating Enzymes Conclusions References 147 147 148 149 151 154 156 156 157 162 163 166 167 167 169 The Retinoblastoma Gene Family in Cell Cycle Regulation and Suppression of Tumorigenesis Jan-Hermen Dannenberg, Hein P J te Riele 183 Cancer and Genetic Alterations 183 The pRb Cell Cycle Control Pathway: Components and the Cancer Connection 184 Cell Cycle Regulation in Mammalian Germ Cells 359 sis was abolished but the phenotypes have not been fully characterized (Kang et al 2002) Genes necessary for repairing the DSBs in meiotic cells are part of the mammalian RAD51 homology dependent pathway RAD51 binds to meiotic chromosomes during chromosome synapsis (Moens et al 1997; Plug et al 1996) and in several meiotic mutants, the number of foci increase, consistent with the proposed role of RAD51 for binding along the DSB and performing the DNA strand invasion search during homologous recombination Due to the embryo lethality conferred by disruptions in the Rad51 genes, a disruption in only one proposed late exchange gene, Dmc1, is currently available to study the role of homologous recombination during meiosis in mammals (Pittman et al 1998; Yoshida et al 1998) Dmc1-deficient males displayed an arrest of gamete development at the pachytene (spermatocyte) stage Oocytes were present in the female fetus, but the chromosomes were unorganized, suggesting a failure in homologous chromosome pairing and synapsis In both sexes, the differentiating cells arrested during the first meiotic division and were eliminated by apoptosis The breast cancer susceptibility gene Brca1 is also essential for recombination during spermatogenesis Brca1-deficient males had defects during pachytene and increased apoptosis (Xu et al 2003) Another group of genes involved in later steps for resolving the DSB intermediates are the mismatch DNA repair genes (Kolas and Cohen 2004) Mismatch repair (MMR) enzymes are involved in fixing mispaired bases and four mouse mutants in MMR genes have been generated Targeted mutagenesis of the mouse Pms2 gene resulted in chromosome synapsis defects in males but not females (Baker et al 1995) A mutation in Mlh1 also caused sex-specific defects; meiotic arrest occurred at the spermatocyte stage in males and exhibited premature chromosome separation (Baker et al 1996; Edelmann et al 1996) Yet, oocytes were able to complete the first meiotic division Mice deficient in Msh4 and Msh5 were sterile and chromosome synapsis defects were also observed (Kneitz et al 2000) The synaptonemal complex (SC) is a zipper-like proteinaceous structure that unites homologous chromosomes during the zygotene stage (Page and Hawley 2004) Mouse mutants in two genes necessary for the SC to assemble have been generated An Sycp3 disruption resulted in male sterility due to chromosome synapsis defects and meiotic arrest, followed by massive apoptotic cell death (Yuan et al 2000) Fertility was only slightly reduced in females However, chromosome missegregation defects increased with maternal aging (Yuan et al 2002) Recently, mutations in Sycp3 were demonstrated to be a cause of human male infertility (Miyamoto et al 2003) and SC defects have been associated with infertility and meiotic arrest at the zygotene stage (Judis et al 2004) A second mouse line, deficient for Sycp1 was infertile with phenotypes similar to Sycp3 mutants observed in males Unlike Sycp3–/– mice, female Sycp1-deficient mice were not fertile (de Vries et al 2005) 360 C Rajesh · D.L Pittman The various genes affecting germ cell development at prophase I are linked to various stages of homologous recombination events: DSB formation, DSB repair, mismatch repair and organization of the synaptonemal complexes The interplay of these gene products are necessary for chromosome alignment and foolproof development of the germ cells Future Perspectives In this chapter, we have provided a summary of mouse models available for studies involving cell cycle regulation during the early events of meiosis Thus far, more than 200 mouse models affecting fertility have been generated that affect the male or female at various stages of gonadal development, germ cell development, maturation, fertilization or embryo development (Naz and Rajesh 2005a,b) For a thorough understanding of cell cycle regulation during mammalian meiosis, more specific strategies are being developed One approach is to generate double knockouts of the available meiotic mutants to further clarify functions in recognition of a cell cycle arrest Examples are generation of Spo11 Dmc1, Spo11 Msh5 and Spo11 Atm double mutant mice, providing insights into epistasis and signaling during prophase I (Di Giacomo et al 2005) A second set of approaches to bypass embryo lethal phenotypes will be the generation of gametogenesis conditional gene disruptions, allelic variants and germline specific RNAi knockdowns in the genes proposed to be involved in meiosis cell cycle regulation (Prawitt et al 2004; Chung et al 2004) A complementary and perhaps less time consuming approach, is the mutagenesis efforts that specifically screen for sterility N-ethylN-nitrosourea (ENU) is used to induce point mutations in spermatogonial stem cells or in ES cells used to generate offspring for phenotype screenings (http://reprogenomics.jax.org/index.html) Methods for ENU mutagenesis and identification of infertile mutants were recently reviewed (Reinholdt et al 2004) The first mutant isolated and cloned using this strategy was Mei1 (meiosis defective 1) and the phenotype of the mutants were similar to the Spo11 knockout mice (Libby et al 2002) The Mei1 gene is unique to mammals, demonstrating the value of the mutagenesis and infertility screening strategies (Libby et al 2003) Identification of a number of new genes and generation of combinations of double or even triple knockouts will help to decipher meiosis cell cycle checkpoint mechanisms (Reinholdt and Schimenti 2005) Finally, in vitro derived sperm cells and oocytes from ES cells will be useful to study early meiosis events (Hubner et al 2003) 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111:369–376 Zindy F, den Besten W, Chen B, Rehg JE, Latres E, Barbacid M, Pollard JW, Sherr CJ, Cohen PE, Roussel MF (2001) Control of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors p18Ink4c and p19Ink4d Mol Cell Biol 21:3244–3255 Subject Index 20S particle, 149 A-box, 153 acetyltransferase, 186 ademomatous polyposis coli (Apc), 103 aging, 258, 263 Ago, 157 allantois, 343, 356 anaphase, 154, 160, 168 anaphase promoting complex/cyclosome (APC/C), 93, 95, 101, 149, 150, 153–156, 158, 160, 163, 164 aneuploidy, 93, 99, 103 APCCdc20 , 153–155, 160, 168 APCCdh1 , 153, 155, 162 Apc11, 152 Apc2, 152 apoptosis, 183, 187, 195–199, 205, 206, 271, 282, 285, 292, 312, 329, 332, 335–337, 345, 354, 355, 357–359 Archipelago, 157 ARF, 333, 334, 336 ARS, 32, 35 Ase1, 150 ATPase, 39–41, 166 atresia, 345 Aurora A, 150, 153 Aurora B, 94, 99, 101, 103, 104 Aurora C, 101, 103 Aurora kinase, 98, 103 bHLH, 209, 210 bipolar attachment, 153 bipolar chromosome attachment, 168 Bmi-1, 262 Bub1, 94, 95, 98, 101, 103, 104 Bub3, 94, 95, 97, 98, 104, 155 BubR1, 94, 95, 97, 98, 103, 104, 155, 164 c-myc, 33, 158, 160 cancer, 159, 183, 211, 227, 259, 271, 272, 276, 294, 295, 297–299, 310, 311 carcinogen, 229 Cdc16, 152 Cdc18, 158 Cdc2, 230, 271–273, 275–280, 282, 293, 300, 301, 303–305, 307, 309, 312, 313 Cdc20, 93, 95, 97, 98, 102, 104, 150, 152–155, 158, 160, 163, 164, 166, 168 Cdc23, 152 Cdc25, 164, 230, 354 Cdc25A, 150, 158, 164, 165 Cdc26, 152 Cdc27, 152 Cdc34, 151 Cdc4, 151, 157–160, 162, 163, 168 – haploinsufficiency of, 160 Cdc42, 162 Cdc45, 43–47 Cdc5/Plk, 150 Cdc53, 151, 152, 156 Cdc6, 36–42, 49, 150, 158 Cdc7, 44, 45 Cdh1, 152, 153, 158, 160, 162 Cdk, 5, 149, 154, 162, 353–356 – activation of, – Cdk2 knockouts, 14 – Cdk3 knockouts, 14 – Cdk4 knockouts, 12 – Cdk6 knockouts, 12 – S phase, 159, 168 Cdk inhibitor (CKI), 159, 161, 162, 166, 168, 230 Cdk1, 149, 159, 161, 164, 165 Cdk2, 153, 159, 164, 165, 184, 185, 187, 188, 193, 196, 208, 232, 259–261, 271–273, 275–286, 289, 293, 294, 296, 298–301, 303–305, 307, 309–313, 334, 335, 353, 354 370 Cdk3, 278, 279 Cdk4, 184, 185, 188, 193, 196, 208, 232, 259–262, 273, 276, 278, 281, 284, 285, 287, 289, 290, 294, 297, 298, 300, 301, 307–313 Cdk6, 184, 232, 260–262, 273, 276, 278, 284, 285, 287, 290, 308–310 CDKN1A, 166 Cdks, 161, 271, 272, 275, 276, 278, 279, 281, 285, 300, 302, 303, 305, 307, 309–311 Cdt1, 36, 37, 40–42, 49, 161, 165 cell cycle, 77, 78, 150, 183–186, 188, 190, 192, 193, 195, 196, 198, 199, 205–207, 210, 271–282, 284–286, 289, 291–296, 298–301, 304, 307–313, 343, 345, 353–358, 360 – Cdc25A, 77, 78 – Cdc7, 78 – Cdk2, 78 – p21, 77 – p53, 77 – yeast, 151 cell cycle engine, 4, – MPF, cell cycle theory, 1, 19 – cell division, – development of, – future of, 23 cell division, 230, 272, 273, 275, 282, 293, 294, 305, 307, 311, 353 cell division cycle (cdc), 147 – mutants, 151, 152 cell growth, – conservation of mass, – mass increase, 22 cell lines, 271, 272, 276–278, 286, 311 cell migration, 271, 301, 303 CENP-E, 94, 97, 98, 101, 102 centrosomes, 293, 301 checkpoint, 4, 42, 46, 47, 93–95, 98, 99, 101–104, 163, 166, 238 – critical size threshold, – DNA damage, 4, 164, 165 – replication, 164 – size threshold, 21 – spindle assembly, 163 – spindle integrity, 163 – stress response, 20 checkpoint signaling, 97, 101 chimaeras, 236 Subject Index Chk1, 164, 165 Chk2, 164, 165 chromatin, 166 chromatin modulation, 66, 81 – 19S proteasome, 81 – histone H2AX, 81 – INO80, 81 – methylation, 81 – NuA4, 81 – ubiquitination, 81 chromosomal instability, 103 chromosomal passeneger complexes, 101 chromosome, 154, 343, 353, 355, 358, 359 chromosome instability, 159 Cin8/Kip1, 150 CKIs, 272 Cks1, 161 Clb2, 150 Clb5, 150 Cln1, 158, 159, 162 Cln2, 158, 159 cohesin, 154 – sister chromatid, 154 cohesion – sister chromatid, 156 crisis, 262, 263 Ctd1, 158, 162 Cul1, 152, 156 Cullin, 151 cyclin, 5, 149, 154, 155, 161, 271–273, 275–277, 279, 280, 283, 284, 288–290, 294, 301, 304, 306–310, 312, 313, 353, 355 – cyclin D knockouts, 13 – cyclin E knockouts, 15 – expression of, – G1, 159 – mitotic, 149, 152, 155 cyclin A, 150, 153, 155, 160, 240, 273, 275–277, 279, 280, 289, 291, 296, 305, 307, 309 cyclin A-Cdk2, 162 cyclin B, 150, 152, 153, 155 cyclin B-Cdk1, 154, 160 cyclin D, 184, 185, 188, 208, 210 – cyclin D knockouts, 13 cyclin D1, 9, 240, 271, 277, 284, 288, 290, 294, 298, 299, 301, 304, 308, 310, 312 cyclin D2, 281, 284, 288, 290, 298, 308 cyclin D3, 240, 243, 288, 290, 291 Subject Index cyclin E, 8, 158, 159, 184, 185, 188, 190, 193, 196, 208, 240, 272, 273, 275–278, 282, 285, 289, 291–293, 296, 298–301, 304, 305, 307, 309–312 – cyclin E knockouts, 15 – regulation of, 10 – substrates of, 11, 18 cyclin-dependent kinase (Cdk), 36–38, 42–45, 48, 50, 51, 230 D-box, 152, 153 Dbf4, 45, 46, 150 deubiquitylating, 149 deubiquitylating enzymes, 167 development, 247, 271, 272, 276, 278, 279, 281, 283–286, 288, 290–292, 294–298, 300, 302, 304, 308–312 DHFR, 33, 34 differentiation, 183, 185, 192, 198, 206–210, 232, 271, 272, 281, 285–287, 291, 292, 294, 297, 300, 308, 311, 312 DNA damage, 37, 38, 45–47, 49, 65, 68, 69, 71, 72, 79, 163, 165, 257, 260, 264, 266 – aphidicolin, 72 – DNA replication interference, 66 – double-strand DNA breaks (DSBs), 66, 69, 71, 79 – HU (hydoxyurea), 72 – ionizing irradiation (IR), 79 – junctions, 71 – MMC (mitomycin C), 79 – MMS (methyl methanesulfonate), 72 – RPA-coated ssDNA, 68, 69 – RPA-ssDNA, 72 – single-stranded DNA (ssDNA), 67 – UV (ultraviolet light), 72 DNA polymerase α, 44 DNA polymerase ε, 40, 47 DNA repair, 66, 73, 77, 79, 80 – base excision repair, 80 – homologous recombination (HR), 76, 79 – mismatch repair, 73, 80 – NER (nucleotide excision repair), 73 – non-homologous end joining [NHEJ], 76, 79 – nucleotide excision repair, 80 DNA replication, 66, 78, 79, 165, 291, 305 – BLM, 79 – Claspin, 78 – Mcm2, 78 371 – Mus81, 79 – RPA, 78 Dpb11, 46, 47 E2F, 9, 153, 160, 183–186, 188–192, 194–200, 205, 208–210, 259–262, 266, 329, 334, 335 – E2F knockout, 17 – function of, 9, 21 E2F/DP, 236 E2F1, 185, 187, 188, 190, 191, 197, 198, 205, 206, 209 E2F2, 188, 190 E2F3, 188, 190 embryogenesis, 285, 290 Embryonic, 291 Emi1, 153, 158, 160 endoreduplication, 291, 293 Esp1, 154 external transcribed spacer, 258 F-box, 156, 157 F-box motif, 156 F-box protein, 151, 156–158, 161, 162 Far1, 158 Fbw7, 157–160, 162, 163 fertility, 345, 354, 360 folliculogenesis, 355–357 G1, 150 G1 arrest, 161 G1 checkpoint, 77 G1 cyclin, 162, 168 G1 phase, 273, 276, 277, 311 G2 phase, 273, 280, 306 G2/M checkpoint, 77 gametogenesis, 343 geminin, 37, 41–43, 50, 150 genomic instability, 160, 238, 257 Gic1,2, 158 Gic2, 162 GINS, 46, 47, 51 granulosa cells, 354, 356 GRB2, 18 growth, 329, 330, 334 Grr1, 157, 162 GSK3β, 159 hCdc4, 157 helicase, 31, 40, 41, 45, 48, 51 hematopoietic, 271, 287, 288, 308, 309, 312 372 histone deacetylases, 186 histone H3, 100 histone methyltransferases, 186 Hsl1, 150 human disease, 230 human papillomavirus (HPV), 228 Id2 (inhibitor of differentiation), 237 immortalization, 193, 195, 196, 258–262 INCENP, 99, 101 inhibitors, 98, 100, 103, 104, 271, 272, 279, 285, 286, 296, 297, 306, 310, 311 initiator, 32, 34, 35, 39 INK4A/ARF, 262, 263 interphase, 353 intra-S checkpoint, 77 Ipl1, 99 KEN-box, 153 kinase, 95, 98, 100, 101, 103 kinase activity, 273, 274, 276, 277, 282, 291, 293, 302, 304, 306, 307, 312 kinetochores, 93–95, 98, 101–103, 163 knockout mice, 12, 229, 260, 265 lamin B2, 33 leucine-rich repeat, 157, 161, 162 Leydig cells, 354 licensing, 37, 40–43, 46, 48, 51 localization, 272, 303, 306 LXCXE motif, 187 M phase, 272, 273, 275, 279, 280, 293, 302, 306, 307 M-phase-promoting factor, 353 Mad, 330 Mad1, 94, 95, 97, 98, 101 Mad2, 94, 95, 97, 98, 101, 104, 155, 164 Mad3, 94, 98, 155, 164 mammalian, 271–274, 276, 278, 279, 284, 287, 313 MAPK, 94, 102 maturation promoting factor (MPF), 230 MCAK, 100 Mcm10, 43, 44, 46, 48, 51 MCM2-7, 38–45, 48, 50, 51 MDM2, 165, 166, 187, 193, 198, 262 mediators, 75, 76 – 53BP1, 75, 76 – Brca1, 75, 76 – Claspin, 75, 76 Subject Index – CtIP, 75 – Mcm7, 75 – Mdc1, 75, 76 – TopBP1, 75 MEFs, 287, 291, 294, 299, 301, 307, 309 meiosis, 156, 279, 281, 282, 285, 304, 343, 345, 353–360 meiosis I, 345 meiosis II, 345 meiotic division – first, 156 – second, 156 meiotic prophase, 345, 353, 354 Met30, 157, 161 Met4, 158, 161, 163, 167 metaphase, 353, 357 metaphase-anaphase transition, 153 methionine, 163 MgcRacGTP, 100 microtubules, 95, 99 mitogen-activated protein kinase, 94, 102 mitosis, 93–95, 97–99, 101–104, 149, 159, 165, 166, 273, 275, 281, 293, 302, 305, 354 – premature entrance into, 160 mitotic checkpoint complex, 93 mitotic checkpoint complex (MCC), 94 mitotic divisions, 353 mitotic spindle, 154, 163 Miz1, 331, 333 mouse, 271, 272, 277–279, 281, 283–285, 288, 290–298, 300, 301, 304, 308, 310, 312, 343, 345, 353, 356–360 mouse embryonic fibroblasts (MEFs), 236 mouse models, 229 Mps1, 94, 101 mutant – cdc, 157 Myc, 190, 192, 195–197, 208, 329–337 negative feedback loop, 166 Nek2A, 150 NLS, 190, 207 Notch, 160 oncogenes, 183 oncogenic transformation, 183, 195, 196, 200, 205, 208, 210 oocytes, 281, 345, 353–360 oogonial stem cells, 345 Orc1, 158 Subject Index origin recognition complex, 32, 34–37 ovary, 286, 300, 302 ovulation, 345, 356, 357 oxidative stress, 257, 263–265 p107, 183, 185, 187–192, 194–196, 198, 199, 205–210, 232 p130, 158, 161, 162, 183, 187–192, 194–196, 198, 199, 205–210, 232 p14ARF , 259, 263, 265 p15INK4B , 241 p16INK4A , 184, 190, 192–194, 196, 197, 199, 240, 241, 285, 290, 309 p18INK4C , 241 p19ARF , 193–199 p19INK4D , 241 p21, 158, 161, 162, 166, 241, 333, 335 p27, 10, 158, 161, 162, 241, 271, 273, 282, 286, 289, 293–301, 303–305, 307, 309–313 – function of, 10, 18 – p27 knockout, 18 – regulation of, 11 p53, 160, 163, 165, 166, 185, 193–199, 205, 206, 210, 229, 257–262, 264, 266 p57KIP2 , 241 pachytene, 353, 354, 356, 358, 359 paclitaxel (Taxol), 104 PCNA, 166, 167 Pds1, 150, 154, 164, 168 phosphatases, 164 phosphodegron, 158–161, 164, 165, 168 – Skp2, 161 phosphorylation, 95, 98, 99, 102, 103, 158, 184, 188–190, 200, 208, 232, 272, 273, 282, 291, 299, 303, 309–311 pituitary, 284–286, 294–297, 301, 305 placenta, 291, 293 Plk, 160, 161 pocket proteins, 185, 187–190, 192, 195, 196, 199, 200, 205–207, 209 polo-like kinase, 160 polycomb, 262 polyploidy, 159 Pop1, 157 Pop2, 157 positive feedback loop, 161 pRb, 183–199, 201, 205–210 pre-initiation complex, 46, 48 pre-replication complex, 48 373 pre-replication complex assembly, 159 primordial germ cells, 343, 358 processing, 71, 73, 74 – Exo1, 72 – exonuclease I, 72 – MRN complex (Mre11-Rad50-Nbs1), 73, 74 proliferation, 271, 287, 288, 290, 294, 296–298, 300, 302, 303, 305, 308–312, 329, 330, 332, 334–337, 354–356 proliferative life span, 263 prometaphase/metaphase arrest, 163 promoters, 186, 188, 190, 194, 209 prophase, 343, 353, 354, 358–360 proteasome, 149, 165–167 – 19S, 149 – 19S regulatory component, 166 – 20S catalytic core, 166 – 26S, 149 protein-ubiquitin ligases, 147, 151, 156 quiescence, 272, 294, 301, 307, 308 quiescent, 272, 278, 291, 294 Rad23, 149 Rad53, 164 Ras, 258, 261, 262, 264, 265 retinoblastoma (Rb), 9, 183, 184, 187, 188, 192, 194, 199, 200, 206–209, 227, 231, 257–260, 262, 266, 273, 279, 282, 284, 291, 292, 294–297, 299, 309–312 – function of, 9, 22 – Rb knockout, 16 – regulation of, 10 Rbx1, 152, 156 redundancy, 271, 272, 307, 313 regulatory particle, 149 replication, 272, 273, 277, 281, 282, 289, 291, 292, 302, 305 – transcription and, 34 – viral, 43, 50 replication factors, phosphorylation of, 36, 37 replication origin, 31–36 replicator, 32, 35, 36 rereplication, 36, 38, 41, 49 restriction point, 7, 273 – cyclohexamide, – early mRNAs, – late mRNAs, – START, 374 RhoA, 18 ring finger motifs, 152, 156 Roc1, 152, 156 ROS, 258, 260, 263–266 Rum1, 158, 159 S phase, 160, 168, 184, 189, 190, 192, 232, 271–273, 276, 278, 279, 284, 286, 289, 292, 296, 299, 301, 305, 307, 309, 311, 312 S-adenosyl methionine (SAM), 161 SAM, 163, 167 Scc1, 154 SCF, 11, 151, 152, 156, 158 SCFβ–TrCP , 160, 164, 165 SCFCdc4 , 158–160, 168 SCFGrr1 , 162 SCFMet30 , 161, 163, 167 SCFPop1/Pop2, 159 SCFSkp2 , 161, 162, 165 securin, 150, 154, 155, 164, 168 seminiferous tubules, 345, 354, 355, 357 senescence, 185, 190, 193, 194, 196, 244, 257–266 sensors, 67 – 9-1-1 complex, 69, 71 – ATR-ATRIP, 67, 68, 71 – Hus1, 69 – Mec1-Ddc2, 67, 68 – Rad1, 69 – Rad17, 69 – Rad17 complex, 71 – Rad9, 69 separase, 154, 168 Sertoli cells, 345, 354, 357 serum starvation, 291, 307, 309 serum stimulation, – Ras/Map kinase pathway, 18 – signal transduction, Sic1, 151, 158, 159, 168 sister chromatid, 154, 156 skin carcinogenesis, 261 Skp1, 151, 156, 163 Skp2, 150, 157, 161, 162, 273, 293, 296 Sld2, 47 Sld3, 45, 46 Slimb, 157 SOS, 18 sperm, 345, 354, 356, 360 spermatocytes, 345, 353–355 Subject Index spermatogenesis, 343, 353, 355, 357, 359 spermatogonia, 345, 353–355 spindle, 93–95, 97–99, 101–104, 154, 168 spindle assembly checkpoint, 93, 99, 101 substrate phosphorylation, 151 SUMO, 166 sumoylation, 166, 167 survivin, 100 Swe1, 158, 161 synapsis, 353, 359 synaptonemal complexes, 354, 359 telomerase, 257, 258, 260, 265 telomere, 80 Telomere attrition, 264 telomere erosion, 262 testis, 281, 282, 284–286, 345, 356 tetratricopeptide repeat, 152 transcription, 166, 355, 356 transcription factors, 183–185, 188, 190, 191, 208–210, 237, 332, 333, 337 transcriptional repressors, 333 transformation, 258, 259, 261, 266 transformed cells, 329 transgenic mice, 229 β-TrCP, 157, 158, 160, 161 tumor, 183, 184, 187, 188, 193, 195–197, 199, 200, 205–208, 210, 227, 271, 284–286, 294, 295, 297–300, 302, 303, 310–312, 329, 333, 335–337 tumor spectrum, 245 tumor suppressor, 183, 187, 205, 206, 257–259, 262, 266 tumorigenesis, 183, 185, 193, 195–197, 199, 200, 205, 207–210 tyrosine 15, 160 Uba domains, 149 Ubc10, 153 ubiquitin, 148, 149 – conjugating enzymes, 147 – ligase, 152 – ubiquitin-mediated proteolysis, 147, 149 ubiquitin conjugating enzyme, 151, 153 ubiquitin-proteasome pathway, 152 ubiquitylation, 153, 155, 161, 165 Ubl domain, 149 WD40 repeat, 157, 158, 160, 161 Wee1, 158, 160, 161, 230 Xkid, 150 ... Institute, NCI-Frederick 1050 Boyles Street Bldg 560 Frederick, MD 2170 2-1 201 USA ISSN 008 0-1 844 ISBN-10 3-5 4 0-3 455 2-3 Springer Berlin Heidelberg New York ISBN-13 97 8-3 -5 4 0-3 455 2-7 Springer Berlin... typical cell cycle DNA replication (S-phase) and cell division (mitosis, M phase) are separated by distinct gap phases Physical and temporal separation of DNA synthesis (S-phase) and mitosis (M phase)... E (1 993) Distinct roles for cyclin-dependent kinases in cell cycle control Science 262:2050–2054 Weinberg RA (1 995) The retinoblastoma protein and cell cycle control Cell 81:323–330 White RJ (2 004)