Fojo | The Role of Microtubules in Cell Biology, Neurobiology, and Oncology | E-Book | sack.de
E-Book

E-Book, Englisch, 587 Seiten, eBook

Reihe: Cancer Drug Discovery and Development

Fojo The Role of Microtubules in Cell Biology, Neurobiology, and Oncology


1. Auflage 2009
ISBN: 978-1-59745-336-3
Verlag: Humana Press
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 587 Seiten, eBook

Reihe: Cancer Drug Discovery and Development

ISBN: 978-1-59745-336-3
Verlag: Humana Press
Format: PDF
Kopierschutz: 1 - PDF Watermark



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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Fojo The Role of Microtubules in Cell Biology, Neurobiology, and Oncology jetzt bestellen!

Zielgruppe


Research

Weitere Infos & Material


An Overview of Compounds That Interact with Tubulin and Their Effects on Microtubule Assembly.- Molecular Mechanisms of Microtubule Acting Cancer Drugs.- Microtubule Dynamics.- Microtubule-Associated Proteins and Microtubule-Interacting Proteins.- The Post-Translational Modifications of Tubulin.- The Isotypes of Tubulin.- The Tubulin Superfamily.- Tubulin Proteomics in Cancer.- Tubulin and Microtubule Structures.- Destabilizing Agents.- Molecular Features of the Interaction of Colchicine and Related Structures with Tubulin.- Antimicrotubule Agents That Bind Covalently to Tubulin.- Microtubule Stabilizing Agents.- Mechanisms of Resistance to Drugs That Interfere with Microtubule Assembly.- Resistance to Microtubule-Targeting Drugs.- Microtubule Stabilizing Agents in Clinical Oncology.- Investigational Anticancer Agents Targeting the Microtubule.- Microtubule Damaging Agents and Apoptosis.- Microtubule Targeting Agents and the Tumor Vasculature.- Neurodegenerative Diseases.- Structure, Function, and Regulation of the Microtubule Associated Protein Tau.


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.



Ihre Fragen, Wünsche oder Anmerkungen
Vorname*
Nachname*
Ihre E-Mail-Adresse*
Kundennr.
Ihre Nachricht*
Lediglich mit * gekennzeichnete Felder sind Pflichtfelder.
Wenn Sie die im Kontaktformular eingegebenen Daten durch Klick auf den nachfolgenden Button übersenden, erklären Sie sich damit einverstanden, dass wir Ihr Angaben für die Beantwortung Ihrer Anfrage verwenden. Selbstverständlich werden Ihre Daten vertraulich behandelt und nicht an Dritte weitergegeben. Sie können der Verwendung Ihrer Daten jederzeit widersprechen. Das Datenhandling bei Sack Fachmedien erklären wir Ihnen in unserer Datenschutzerklärung.