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The Role of Microtubules in Cell Biology, Neurobiology, and Oncology (eBook)

Antonio Tito Fojo (Herausgeber)

eBook Download: PDF
2009 | 2008
XVII, 587 Seiten
Humana Press (Verlag)
978-1-59745-336-3 (ISBN)

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This book presents the first comprehensive exploration of the dynamic potential of microtubules anti-cancer targets. Written by leading anti-cancer researchers, this groundbreaking volume collects the most current microtubule research available and investigates the potential of microtubules in cancer therapy.


I want to thank all who contributed to this first edition for their hard work and professionalism, and especially for their patience. I hope the readers will find this volume as helpful as I have found it. There is no doubt that the family of proteins we call the tubulins and the microtubules that they form when they aggregate are extremely important in the cell and, as we are increasingly learning, important in diseases that afflict so many. This field of investi- tion is a testament to how important both basic and clinical sciences are in understanding disease mechanisms and making inroads into therapies. Without the basic science knowledge that has been accumulated, to which the authors of this work have contributed greatly, we would not be in the position we find ourselves of increasingly understanding disease and advancing therapies. As I read the chapters, I was humbled to think of the insights that so many have contributed to this field, and again became aware of how the collaborative effort of so many is needed to understand the complexities of nature. By working together, many have helped to advance this field. Because of their efforts, we find ourselves with the wealth of knowledge contained in this book. This knowledge gives us so much insight even as it challenges us to continue working. Thanks again to all of the wonderful collaborators for their excellence and their patience. Tito Fojo, MD, PhD vii CONTENTS Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. An Overview of Compounds that Interact with Tubulin and their Effects on Microtubule Assembly.

Ernest Hamel



2. Molecular Mechanisms of Micotubule Acting Cancer Drugs.

J. J. Correia and S. Lobert



3. Microtubule Dynamics: Mechanisms and Regulation by Microtubule-Associated Proteins and Drugs in vitro and in cells

Mary Ann Jordan and Leslie Wilson



4. Microtubule Associated Proteins (MAPs) and Microtubule Interacting Proteins: Regulators of Microtubule Dynamics

Maria Kavallaris, Sima Don, Nicole M. Verrills



5. The Post-Translational Modifications of Tubulin

Richard F. Ludueña, and Asok Banerjee



6. The Isotypes of Tubulin: Distribution and Functional Significance

Richard F. Ludueña, and Asok Banerjee



7. The Tubulin Superfamily

Richard F. Ludueña, and Asok Banerjee



8. Tubulin Proteomics in Cancer

Pascal Verdier Pinard, Fang Wang, Ruth Hogue Angeletti , Susan Band Horwitz, and George A. Orr



9. Tubulin and Microtubule Structures

Eva Nogales and Kenneth H. Downing



10. Destabilizing Agents: Peptides and Depsipeptides

Lee M. Greenberger and Frank Loganzo



11. Molecular Features of the Interaction of Colchicine and Related Structures with Tubulin

Susan L. Bane



12. Antimicrotubule Agents that Bind Covalently to Tubulin

Dan L. Sackett



13. Microtubule Stabilizing Agents

Susan Band Horwitz and Tito Fojo



14. Mechanisms of Resistance to Drugs that Interfere with Microtubule Assembly

Fernando Cabral

15. Resistance to Microtubule Targeting Drugs: Part II

Paraskevi Giannakakou and James P. Snyder



16. Microtubule Stabilizing Agent in Clinical Oncology: The Taxanes

Chris H. Takimoto and Muralidhar Beeram



17. Investigational anti-cancer agents targeting the microtubule.

Lyudmila A. Vereshchagina, Orit Scharf, and A. Dimitrios Colevas



18. MicrotubuleDamaging Agents and Apoptosis

Manon Carre and Diane Brauger



19. Microtubule targeting agents and the tumor vasculature

Raffaella. Giavazzi, K. Bonezzi and Giulia Taraboletti



20. Neurodegenerative Diseases: Tau Proteins in Neurodegenerative Diseases Other Than Alzheimer's Disease

André Delacourte, Nicolas Sergeant and Luc Buée



21. Structure, Function and Regulation of the Microtubule Associated Protein Tau

Janis Bunker and Stuart C. Feinstein

2. MICROTUBULE ASSEMBLY (S. 24-25)

Microtubules are polar cytoskeletal structures with a plus (+) and minus (–) end (see Chapter 10 in this book) comprised of aß-tubulin heterodimers organized head-to-tail (aßaß) along (typically 12–15) protofilaments that laterally contact to make a closed lattice. The molecular structure of a microtubule is derived from electron crystallography on (antiparallel and inverted) Zn-induced sheets (17) that were later docked into a 20 Å reconstruction of the microtubule lattice (18).

Refined structures have been described (19–22). Assembly requires an unfavorable in vitro nucleation step (off ?-tubulin bound to centrosomes in vivo) and GTPMg bound to tubulin where GTP becomes nonexchangeable when buried in the lattice. GTP hydrolysis occurs at this buried longitudinal interface between dimers with the a-Glu254 catalytic group residing on the previous dimer in the protofilament (23) Thus, GTP hydrolysis is necessarily linked to assembly, but only in polymers with straight quaternary structures like microtubules. (The role of association in hydrolysis and the importance of the a-Glu254 catalytic group is not universally appreciated in the field. GTP hydrolysis requires tubulin association, but tubulin association does not necessarily cause GTP hydrolysis.)

The polar structure of the microtubule requires that subunit addition at the + end involves formation of a aßGTPaßGTP (+) linkage ([+] indicates + end of the microtubule) where the buried GTP can be cleaved but the exposed ßGTP is a site for subunit addition. At the – end subunit addition involves formation of a (–)aßGTPaßGDP linkage ([–] indicates – end of the microtubule) where the newly buried GTP can be cleaved and an exposed a-chain is the site for subunit addition. The presence of GTP hydrolysis thus produces two distinct ends, a + end that is growing by producing an exposed nucleotide site (24), and a – end that is growing by burying a ßGTP that can be immediately cleaved.

This gives rise to microtubule ends with distinct stability (see discussion below and ref. 24). The nucleotide at the + end is directly exchangeable with free nucleotide (25), whereas the nucleotide at the – end is nonexchangeable and requires tubulin dissociation before exchange. These features are represented in the model of a microtubule protofilament shown in Scheme 1. In this mechanism the aßGTP added at the – end undergoes hydrolysis, albeit at some rate, while the aßGTP added at the + end is a site for further growth and can only undergo hydrolysis when buried by another tubulin heterodimer. Lateral interactions not depicted here are also known to strongly influence the cooperativity of assembly (see Fig. 2) and the rate of hydrolysis is dependent upon the quaternary structure of the MT end.

Erscheint lt. Verlag 14.1.2009
Reihe/Serie Cancer Drug Discovery and Development
Cancer Drug Discovery and Development
Zusatzinfo XVII, 587 p.
Verlagsort Totowa
Sprache englisch
Themenwelt Medizin / Pharmazie Medizinische Fachgebiete Onkologie
Medizin / Pharmazie Studium
Naturwissenschaften Chemie
Technik
Schlagworte Apoptosis • Biology • Cell Biology • Distribution • Isotop
ISBN-10 1-59745-336-6 / 1597453366
ISBN-13 978-1-59745-336-3 / 9781597453363
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