Table Of ContentMOLECULAR BIOLOGY
INTELUGENCE
UNIT
Intermediate Filaments
Jesus M. Paramio, Ph.D.
Department of Molecular and Cell Biology
CIEMAT
Madrid, Spain
LANDES BIOSCIENCE / EuREKAH.coM SPRINGER SCIENCE+BUSINESS MEDIA
GEORGETOWN, TEXAS NEW YORK, NEW YORK
U.S.A. U.SA
INTERMEDIATE FILAMENTS
Molecular Biology Intelligence Unit
Landes Bioscience / Eurekah.com
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ISBN: 0-387-33780-6 Printed on acid-free paper.
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Libraiy of Congress Cataloging-in-Publication Data
Intermediate filaments / [edited by] Jesus M. Paramio.
p. ; cm. ~ (Molecular biology intelligence unit)
Includes bibliographical references and index.
ISBN 0-387-33780-6 (alk paper)
1. Cytoplasmic filaments. I. Paramio, Jesiis M. II. Series:
Molecular biology intelligence unit (Unnumbered)
[DNLM: 1. Intermediate Filament Proteins. 2. Gene Expression.
3. Keratin-physiology. QU 55 1609 2006]
QH603.C95I58 2006
611'.0181-dc22
2006009316
CONTENTS
Preface ix
Desmin and Other Intermediate Filaments in Normal
and Diseased Muscle 1
Denise Paulin and Zhigang Xue
Desmin in Mature Skeletal and Heart Muscle Cells 1
Desmin and Other IF Proteins in Different Muscles 2
Functions of Desmin in Striated Muscles 4
Function of Desmin in Smooth Muscles 5
Gene Regulation 5
Desmin-Related Myopathies (DRM) 6
Intermediate Filaments in Astrocytes in Health
and Disease 10
Milos Pekny and Ulrika Wilhelmsson
IFs in Astroglial Cells during Development 10
GFAP znd Its Regulation 11
Vimentin and Nestin and Their Regulation 13
Formation of IFs in Astroglial Cells 13
Astrocyte IFs, CNS Trauma and Regeneration 16
Astrocyte IFs and Resistance to Mechanical Stress 22
Astrocyte IFs, Osmotic Stress and Ischemia/Hypoxia 25
Astrocyte IFs, Cell Proliferation and Tumorigenesis 25
GFAP Mutations and Alexander Disease 26
Neuronal Intermediate Filaments
and Neiu-odegenerative Diseases 35
Gee Y. Ching and Ronald K.H. Liem
Neuronal Intermediate Filament Proteins 36
Neuronal IFs in Neurodegenerative Diseases 38
Neurofilaments: Phosphorylation
and Signal Transduction 52
Sashi Kesavapany, Richard H. Quarks and Harish C. Pant
Neurofilaments Are Members of the Intermediate
Filament Family 53
Neurofilaments and Axonal Caliber 55
Phosphorylation of Neurofilaments 55
Neurofilaments and Their Associated Kinases 56
Neurofilament Tail Domain Phosphorylation 57
Axonal Transport of Neurofilaments 58
Phosphorylation of NFs and Disease 59
Neurofilaments and Signal Transduction Pathw^ays 60
5. Keratin Intermediate Filaments and Diseases of the Skin 74
E. Birgitte Lane
Epidermal Blistering Caused by Keratin Mutations 7A
Candidate Genes in Other Epithelia 75
From Candidate Genes to "Candidate Diseases" 77
Supramolecular Stability versus Molecular Flux 77
Keratin Filaments as Tensile Structures 78
Significance of Keratin Role in Skin Fragility Disorders 79
6. The Keratin K6 Minifamily of Genes 83
Manuel Navarro
Conservation of Sequence in the K6 Polypeptides 84
Expression of the K6 Genes 87
Expression and Partners 89
Functional Considerations 89
7. Transcriptional Regulation of Keratin Gene Expression 93
Miroslav Blumenberg
Transcriptional Regulation of Keratin K5 Expression 93
Regulation of Kl4 95
Regulation of Kl 5 96
Regulation of Kl and KIO 96
Regulation of K4 and K13 97
Regulation of K3 and K12 98
Regulation of Hair Keratins 99
Regulation of Keratin Gene Expression
by Hormones and Vitamins 99
Regulation of Keratin Gene Expression
by Growth Factors and Cytokines 101
Regulation of Small Keratins, K7, K8, K18 and K19 101
Specific Transcription Factors Implicated in Regulation
of Transcription of Keratin Genes 103
Conclusions and Future Directions 105
8. Simple Epithelial Keratins: Expression, Function and Disease 110
M. Llanos Casanova, Ana Bravo andjosi L. Jorcano
Suggested Functions of Simple Epithelial Keratins Ill
Simple Epithelial Keratin Proteins and Disease 114
Altered Simple Epithelial Keratin Expression and Cancer 115
9. Keratins as Targets in and Modulators of Liver Diseases 120
Kurt Zatloukal, Conny Stumptner, Andrea Fuchsbichler
and Helmut Denk
The Keratin Cytoskeleton of Hepatocytes
and Bile Duct Epithelial Cells 120
Alterations of the Keratin Cytoskeleton
in Human Liver Diseases 121
Animal Models to Study Hepatocytic Keratin Alterations 122
Mallory Bodies as a Product of the Cellular Response
to Misfolded Keratin 124
How Can Keratins Influence Toxic Cell Injury? 125
Mutations of Keratin Genes and Liver Diseases 127
10. The Search for Specific Keratin Functions:
The Case of Keratin KIO 131
Mirentxu Santos, Carmen Segrelles, Sergio Ruiz,
M. Fernanda Lara and Jesus M. Paramio
Keratin KIO Assembly and Dynamics 132
Keratin KIO Inhibits Cell Proliferation 134
Transgenic Mice Models to Study KIO Functions 138
The Paradigms ofKlO Knock Out Model 139
Reconciling Hypotheses 141
Index 147
- ViTWTTWi 1
-bUl 1 wK 1
J esiis M. Paramio
Department of Molecular and Cell Biology
CIEMAT
Madrid, Spain
Email: je [email protected]
Chapter 10
I — —^ r^O^TT'^TTJT rnrr^ T>c \\
• K^VJ
Miroslav Blumenberg Andrea Fuchsbichler
The Departments of Dermatology Institute of Pathology |
and Biochemistry Medical University of Graz
and Graz, Austria
The Cancer Institute Chapter 9
NYU School of Medicine
New York, New York, U.S.A. Jos^ L. Jorcano
Email: blumem01@ med.nyu.e du Department of Molecular
Chapter 7 and Cell Biology
CIEMAT
Ana Bravo Madrid, Spain
Department of Animal Pathology Email: [email protected] 11
Veterinary School of Lugo Chapter 8
University of Santiago de Compostela 11
Madrid, Spain Sashi Kesavapany
Chapter 8 Laboratory of Neurochemistry,
National Institute of Neurological
M. Llanos Casanova Disorders and Stroke
Department of Molecular National Institute of Health
and Cell Biology Bethesda, Maryland, U.S.A.
CIEMAT Chapter 4
Madrid, Spain
Email: llanos.casanova@ciemat. es E. Birgitte Lane
Chapter 8 Cancer Research UK Cell Structure
Research Group
Gee Y. Ching Cell and Developmental Biology Division
Departments of Pathology and Anatomy University of Dundee
and Cell Biology School of Life Sciences
Columbia University College Dundee, U.K.
of Physicians and Surgeons Email: [email protected]
New York, New York, U.S.A. Chapter 5
Chapter 3
M. Fernanda Lara
Helmut Denk Department of Molecular
Institute of Pathology and Cell Biology
Medical University of Graz CIEMAT
Graz, Austria Madrid, Spain
Chapter 9 Chapter 10
Ronald K.H. Liem Sergio Ruiz
Departments of Pathology and Anatomy Cancer Research Center
and Cell Biology University of Salamanca
Columbia University College Salamanca, Spain
of Physicians and Surgeons Chapter 10
New York, New York, U.S.A.
Email: [email protected] Mirentxu Santos
Chapter 3 Department of Molecular
and Cell Biology
Manuel Navarro CIEMAT
Department of Molecular Madrid, Spain
and Cell Biology Chapter 10
CIEMAT
Madrid, Spain Carmen Segrelles
Email: [email protected] Department of Molecular
Chapter 6 and Cell Biology
CIEMAT
Harish C. Pant Madrid, Spain
Laboratory of Neurochemistry Chapter 10
National Institute of Neurological
Disorders and Stroke Conny Stumptner
National Institute of Health Institute of Pathology
Bethesda, Maryland, U.S.A. Medical University of Graz
Email: [email protected] Graz, Austria
Chapter 4 Chapter 9
Denise Paulin Ulrika Wilhelmsson
Biologic Mol^culaire de la DifF^renciation Department of Medical Biochemistry
Paris, France Sahlgrenska Academy
Email: [email protected] at Goteborg University
Chapter 1 Goteborg, Sweden
Chapter 2
Milos Pekny
Department of Medical Biochemistry Zhigang Xue
Sahlgrenska Academy Biologic Mol^culaire de la Diff^renciation
at Goteborg University Paris, France
Goteborg, Sweden Chapter 1
Email: [email protected]
Chapter 2 Kurt Zadoukal
Institute of Pathology
Richard H. Quarles Medical University of Graz
Laboratory of Molecular Graz, Austria
and Cellular Neurobiology Email: [email protected]
National Institute of Neurological Chapter 9
Disorders and Stroke
National Institute of Health
Bethesda, Maryland, U.S.A.
Chapter 4
-PREFACE --
M
olecular biologists' concept of cells is a "biological container" where
important molecules float and interact with one another more or
less randomly. However, a close view of this "bag" reveals an as
tonishing net of fibrous proteins crossing throughout the cytoplasm: the
cytoskeleton. This structure is composed of three different elements: actin
microfilaments, tubulin microtubules, and a third class denoted, due to
their size, intermediate filaments (IF). This last network is built by different
proteins in different cells types, forming the largest family of cytoskeletal
proteins. They are divided into six categories and, except for type V, the
lamins, they all form a cytoplasmic web. Types I and II include the epithelial
keratins and comprise more than 20 different polypeptides. Type fflf includes
vimentin (expressed in cells of mesenchymal origin), desmin (characteristic of
muscle cells), GFAP (in glial cells) and peripherin (in the peripheral nervous
system). Type IV IF proteins are found in neurones and include the
neurofilament proteins (NF-L, NF-M and NF-H) and a-internexin. Type
VI may include, depending on different group criteria, nestin, synemin,
paranemin and tanabin. The function of these proteins has long been associ
ated with a structural role. However, this common function does not explain
their tissue- and differentiation-specific expression patterns. Evidence is now
emerging that IF act as an important framework for the modulation and
control of essential cell processes.
In this book, research groups summarize their findings in the IF field
in particular focusing on the possible functional roles of IF proteins in cells
and their relevance in pathological situations. Paulin's and Pekny's groups
summarize these aspects in desmin and GFAP, respectively. In other words,
how the functions of muscle cells and astrocytes are dependent on IF. The
neurofilaments are covered in two chapters by Pant's and Liem's groups.
They focus on mutation and phosphorylation of these proteins and their
relationship with neurodegenerative disorders in mouse models and humans.
Keratins, the largest subfamily of IF proteins, are expressed in epithelial
cells. Remarkably, the expression of different keratins is strictly regulated in
tissue- and differentiation-specific patterns. In this case, data obtained in
transgenic mice and genetic analyses of human hereditary syndromes in the
early nineties clearly demonstrated that keratins provide cells with mechani
cal resilience against physical stress. This is reviewed in Lane s chapter. How
ever, there are many intriguing questions to be solved with respect to these
proteins. The diversity of keratins is highlighted in the chapter by M. Navarro.
He concentrates on the keratin K6 minifamily, in which minimal differences
can be observed, discussing the hints about their possible different biological
functions. The transcriptional mechanisms regulating keratin expression,
which ultimately gives rise to their characteristic expression pattern, are
reviewed in M. Blumenberg's chapter.
As commented above, the function of keratins as essential mediators
of structural integrity was proposed as a result of the discovery of point
mutations in human keratin genes in patients suffering from different epi
thelial disorders. However, this is only the overall function of the stratified
epithelia keratins. Aspects relative to the functions of simple epithelia keratins
are covered by two chapters. Zatloukal et al summarize the role of these
keratins in chronic liver diseases. Casanova et al review the functionality of
keratins K8 and K18 as putative modulators of signaling and apoptosis and
their relationship with tumor development and progression. Finally, in the
chapter by Santos et al we summarize our findings which suggest that kera
tin KIO is a mediator of keratinocyte homeostasis.
Overall this book reviews most recent developments in this growing
and exciting field and will help those interested in the study of these inter
esting proteins.
Jesus M. Paramioy Ph.D.
CHAPTER 1
Desmin and Other Intermediate Filaments
in Normal and Diseased Muscle
Denise Paulin* and Zhigang Xue
Abstract
T
he intermediate filament proteins (desmin, vimentin, nestin, synemins and paranemin)
synthesized by muscle cells depends on the type of muscle and its stage of development.
Desmin is present in all muscles at all stages of development. The others appear
transiently or in only certain muscles. The muscles of mice lacking desmin and those of
human having a mutated desmin gene that encodes a nonfunctional desmin are abnormal.
The severity of the human disease depends on the location of the mutation; it may cause
skeletal myopathies, cardiomyopathies or altered vascular elasticity. This report summarizes
the function of the desmin gene in the skeletal and smooth muscles, the gene regulation and
desmin-related myopathies.
Desmin in Mature Skeletal and Heart Muscle Cells
The cytoskeleton of muscle cells includes proteins whose primary function is to link and
anchor structural cell components, especially the myofibrils, the mitochondria, the sarcotubular
system and the nuclei.^ The cytoskeleton has three major filamentous components, interme
diate filaments (IFs); microfilaments (actin); and microtubules. The IFs are so named be
cause their diameter (8-10 nm) is intermediate between those of the thick (myosin, 15 nm)
and thin (actin, 6 nm) filaments. The cytoskeleton may also be subdivided into the
extra-sarcomeric, the intra-sarcomeric and the subsarcolemmal cytoskeleton; the IFs form
the extra-sarcomeric cytoskeleton.
Desmin is the main IF protein in mature skeletal and heart muscles. It is encoded by a fully
characterized single copy gene, which has been mapped to band q35 to the long arm of hu
man chromosome 2 and to band C3 of the mouse to chromosome 1. Desmin is one of the
first muscle-specific proteins to be detected in the mammalian embryo, appearing before titin,
skeletal muscle actin, myosin heavy chains and nebulin. It can be detected at 8.5 d.p.c. in the
developing mouse embryo, in the ectoderm where it is transiendy coexpressed with keratin and
vimentin. The protein is also found in the heart rudiment on 8.5 d.p.c, and its concentration
increases over time, continuing in the myocardial cells during later cardiogenesis. From 9
d.p.c. onwards, desmin can be detected in the myotomes.
The concentration of desmin in skeletal and cardiac muscles remains high throughout em-
bryogenesis and early posmatal life. There is much more desmin in heart muscle cells (2% of total
protein) than in skeletal muscle cells (0.35%) of mammal. It forms a three-dimensional scaffold
around the myofibrillar Z-disc and interconnects the entire contractile apparatus with the
subsarcolemmal cytoskeleton, the nuclei and other cytoplasmic organelles (Fig. 1). Desmin also
*Corresponding Author: Denise Paulin—Biologie Moleculaire de la Differenciation,
Paris Cedex, France. Email: [email protected]
Intermediate Filaments, edited by Jesus Paramio. ©2006 Landes Bioscience
and Springer Science+Business Media.
