* Topics covered include the mammalian circadian proteins, cell death, tumor progression, and more
* Latest volume in the series that covers six reviews in more than 250 pages
* Includes many descriptive figures
* Topics covered include the mammalian circadian proteins, cell death, tumor progression, and more
* Latest volume in the series that covers six reviews in more than 250 pages
Current Topics in Developmental Biology provides a comprehensive survey of the major topics in the field of developmental biology. These volumes are valuable to researchers in animal and plant development, as well as to students and professionals who want an introduction to cellular and molecular mechanisms of development. The series has recently passed its 30-year mark, making it the longest-running forum for contemporary issues in developmental biology. Includes many descriptive figures Topics covered include the mammalian circadian proteins, cell death, tumor progression, and more Latest volume in the series that covers six reviews in more than 250 pages
Front Cover 1
Current Topics in Developmental Biology 4
Copyright Page 5
Contents 6
Contributors 10
Chapter 1: Contribution of Membrane Mucins to Tumor Progression Through Modulation of Cellular Growth Signaling Pathways 12
I. Mucin Structure, Function, and Involvement in Tumor Progression 13
A. Mucin Structure 13
B. Membrane Mucins and Tumor Progression 15
II. MUC1 Contributions to Tumor Cell Growth Signaling 16
A. Signaling by ErbB RTKs 17
B. MUC1 Interaction with EGFR 18
C. MUC1 Interaction with beta-Catenin 18
D. Other MUC1 Growth Regulatory Mechanisms 20
E. Mouse Models of MUC1 Action 20
III. MUC4 Contributions to Tumor Cell Growth Signaling 21
A. Alteration of ErbB2 Localization by MUC4 Interaction 22
B. MUC4-Mediated Tumor Growth and Metastasis 24
IV. Inhibition of Signaling by Mucins 25
V. Perspectives 26
References 27
Chapter 2: Regulation of the Epithelial Na+ Channel by Peptidases 34
I. Introduction 35
II. ENaC Regulation by Peptidases: In Vitro and Biochemical Evidence 36
A. Inhibition of Na+ Transport in Epithelial Monolayers by Antipeptidases 36
B. Peptidases in ENaC Maturation and Disposal 37
C. CAPs in Mammalian Epithelia 39
D. Candidate Physiological Inhibitors of ENaC-Activating Peptidases 41
III. ENaC Regulation by Peptidases: In Vivo Evidence 42
A. Regulation of Alveolar Na+ and Water Transport by Serine Peptidases 42
B. Regulation of Colonic Prostasin Expression by Aldosterone and Dietary Na+ 44
C. Regulation of Prostasin by Aldosterone in the Kidney 45
D. Potential Role of Prostasin in Regulating Aldosterone Production and Hypertension 48
E. Role of CAPs in Maintaining the Epidermal Permeability Barrier 48
F. ENaC Dysregulation in the Pathophysiology of Cystic Fibrosis: CAPs as Potential Drug Targets 50
References 52
Chapter 3: Advances in Defining Regulators of Cementum Development and Periodontal Regeneration 58
I. Introduction 59
II. Question 1. What Are the Unknowns That Must Be Considered in Order to Replicate the Enamel (Crown) and How Do the Proteins Involved in Crown Development Relate to Root Development? 62
A. Enamel Structure 62
B. Enamel Biomineralization: Role of Proteins 63
C. Future Prospects for Enamel Regeneration 69
III. Question 2. What Do We Know About the Cells Required for Periodontal Development and Regeneration? 74
A. Developmental Cells 74
B. Derivation of Cementum: Competing Theories of Cementoblast Origin 76
C. Differences Between Cementoblasts and Osteoblasts 80
D. Tooth Stem Cell Populations 83
IV. Question 3. What Genes and Associated Proteins Are Important for Root/Periodontal Tissue Formation? 87
A. Factors Associated with the Putative Epithelial Niche (HERS and ERM) and Surrounding Mesenchyme 88
B. Bone Morphogenetic Proteins 92
C. Periostin and Nuclear Factor I-C/CAAT Box Transcription Factor 97
D. Regulators of Phosphate and Pyrophosphate Metabolism 98
E. Factors Known to Regulate Osteoprogenitor Cells and Osteoblasts 102
F. Emerging and Other Factors to Consider 104
V. Conclusions and Future Directions 112
Acknowledgments 114
References 114
Chapter 4: Anabolic Agents and the Bone Morphogenetic Protein Pathway 138
I. Introduction 139
II. Bone Metabolism 142
A. Bone Anabolic Growth Factors 143
B. Platelet-Derived Growth Factor 143
C. Transforming Growth Factor beta 144
D. Fibroblast Growth Factors 144
E. Vascular Endothelial Growth Factors 145
F. Growth Hormone/Insulin-Like Growth Factors 145
G. Bone Morphogenetic Proteins 146
III. The BMP Pathway and Bone Anabolic Therapies 146
A. BMP/SMAD Signaling Pathway 147
B. Agents That Act on the BMP Pathway 148
C. Agents That Do Not Act on the BMP Pathway 160
IV. Conclusions and Future Directions 164
References 165
Chapter 5: The Role of Mammalian Circadian Proteins in Normal Physiology and Genotoxic Stress Responses 184
I. Introduction 185
II. Circadian Rhythms and the Organization of the Mammalian Circadian System 186
III. Molecular Organization of the Circadian Oscillator in Mammals 187
A. The Molecular Circadian Oscillator Is Composed of Multiple Interacting Loops 187
B. Posttranslational Regulation of the Components of the Molecular Circadian Oscillator 191
C. Peripheral Clocks and Circadian Control of Gene Expression in Different Tissues 195
IV. Human Disorders Associated with Altered Function of the Circadian System 196
A. Sleep Disorders 196
B. Jet Lag and Shift Work Maladaptation Syndromes 198
C. Seasonal Affective Disorder 199
D. Mood Disorders 200
V. Pathologies and Developmental Defects in Circadian Mutant Mice 201
A. CLOCK 201
B. BMAL1 203
C. NPAS2 205
D. PERIODs 206
E. TIMELESS 207
F. CRYPTOCHROMEs 208
G. REV-ERBalpha 208
H. Circadian Proteins, Organism-Environment Interaction, and Pathologies: A Hypothesis 209
VI. Circadian Control of the Organism's Response to Genotoxic Stress 211
A. Chronotherapy of Cancer 211
B. The Sensitivity of Normal Cells to Genotoxic Drugs Depends on the Functional Status of the CLOCK/BMAL1 Transactivation Complex 213
C. Molecular Determinants of Sensitivity to Anticancer Therapy 214
D. Functional Interplay Between the Circadian and Stress Response Systems: A Model 215
VII. Circadian Proteins as Targets for Therapeutic Intervention 218
Acknowledgments 218
References 218
Chapter 6: Autophagy and Cell Death 228
I. Introduction 229
II. Description of Programed Cell Death Morphologies 229
III. Autophagic Cell Death 230
A. Autophagy May Kill: Molecular Evidence 230
B. How Does Autophagy Kill? 232
IV. Autophagy and Autophagic Cell Death Regulatory Mechanisms 233
A. Class III Phosphatidylinositol 3-Kinase, Beclin-1, and Autophagy 234
B. Two Ubiquitin-Like Pathways Involved in Autophagic Vesicle Formation 235
C. The Tor Pathway 236
D. Class I Phosphatidylinositol 3-Kinase and Autophagy 237
E. Protein Transcription/Translation-Related Pathways 238
F. G Proteins 240
G. DAPk Family 240
H. Sphingolipid Pathways 241
I. Role of Mitochondria and the Bcl-2 Family Proteins in Autophagy 242
J. RIP Protein-Related Pathways and Autophagic Cell Death 244
V. Autophagy-Apoptosis Crosstalks 245
VI. Survival Versus Death Aspects of Autophagy 247
VII. Conclusions 248
Acknowledgments 249
References 249
Index 258
Contents of Previous Volumes 266
Contribution of Membrane Mucins to Tumor Progression Through Modulation of Cellular Growth Signaling Pathways
Kermit L. Carraway, III; Melanie Funes; Heather C. Workman; Colleen Sweeney UC Davis Cancer Center, Sacramento, California 95817
Abstract
Mucins are large, heavily O-glycosylated proteins expressed by epithelial tissues. The canonical function of membrane mucins is to provide protection to vulnerable epithelia by forming a steric barrier against assault, and by contributing to the formation of protective extracellular mucin gels. The aberrant overexpression of mucins is thought to contribute to tumor progression by allowing tumor cells to evade immune recognition, and by aiding in the breakdown of cell–cell and cell–matrix contacts to facilitate migration and metastasis. Recent evidence suggests that we should now modify our thinking about mucin function by considering their roles in signaling pathways leading to cellular growth control. Here we review the markedly divergent mechanisms by which membrane mucins, specifically MUC1 and MUC4, influence pathways contributing to cellular proliferation and survival. The cytoplasmic domain of MUC1 serves as a scaffold for the assembly of a variety of signaling proteins, while MUC4 influences the trafficking and localization of growth factor receptors, and hence their responses to external stimuli. We also discuss how tumor cells exploit these mechanisms to promote their own growth and metastasis.
I Mucin Structure, Function, and Involvement in Tumor Progression
Mucins and mucin-like proteins comprise a family of large transmembrane or secreted glycoproteins that are commonly associated with epithelial tissues (Strous and Dekker, 1992), but are also present at the surfaces of other selected cell types. Mucins are the major glycoprotein components of the mucous layer coating the cells lining the respiratory, digestive, and urogenital tracts, and are also prominently expressed by the ocular epithelium. Mucins possess specific domains that promote their oligomerization into viscous solutions or gels. In addition, their extensive O-glycosylation contributes to a high negative charge and a rigid and extended protein conformation, resulting in steric and charge repulsion of cells or other molecules (Jentoft, 1990). These properties allow mucins to function in protecting epithelial tissues from infection, dehydration, and physical or chemical assault, and to serve as a lubricant for tissues exposed to mechanical stresses (Perez-Vilar and Hill, 1999). The observed expression of mucins by vascular endothelial cells (Zhang et al., 2005) suggests that they may contribute to the formation of poorly adhesive surfaces in the lumen of blood vessels, augmenting blood flow by suppressing the counterproductive binding of blood components. On the other hand, some mucin glycosyl groups can serve as ligands for selectins and other cell adhesion molecules, promoting cell–cell interactions. In this context, mucin expression on the leading edge of activated T cells (Correa et al., 2003) suggests that mucins could also play a role in extravasation during inflammation.
A Mucin Structure
The unifying structural feature of all mucins and mucin-like proteins is that they express O-linked glycans in serine- and threonine (Ser/Thr)-rich clusters in their extracellular regions. A major subset of the mucins, a subfamily of proteins encoded by at least 20 distinct genes (designated MUC1–MUC20), contain Ser/Thr-rich tandem repeats of 8 to 59 amino acid residues in length, depending on the identity of the mucin (Baldus et al., 2004a). Repeats are heavily O-glycosylated, such that typically greater than 50% of mucin mass is O-linked oligosaccharide. N-linked glycans are also often present in mucins but to a much lesser degree. The number of Ser/Thr-rich repeats encoded by a particular mucin gene can vary markedly among individuals due to genetic polymorphism, and variable number tandem repetition (VNTR) polymorphisms in mucins are associated with susceptibility to various diseases (Fowler et al., 2001). Moreover, mucin glycosylation patterns are tissue and cell type dependent, and can be altered with cellular differentiation state or with neoplastic transformation. Aberrant mucin glycosylation occurs in essentially all types of human cancers and is associated with tumorigenecity and metastasis (Moniaux et al., 2004). Many glycosyl epitopes are tumor-associated antigens and have been used in diagnosis and immunotherapy.
Mucins are divided into three subgroups: the gel-forming, soluble, and transmembrane mucins. The gel-forming mucins, composed of MUC subfamily proteins MUC2, MUC5AC, MUC5B, MUC6, and MUC19, are characterized by the presence of several cysteine-rich domains in their extracellular regions (Chen et al., 2004). A single C-terminal cysteine-knot (CTCK) domain may be involved in the dimerization of these mucins. Trypsin inhibitor-like (TIL) domains and von Willebrand factor C (VWC) or D (VWD) domains are commonly found in a variety of extracellular proteins and may be involved in specific protein–protein interactions that contribute to the gel-forming properties of these mucins. Gel-forming mucins are typically expressed by specialized glands or goblet cells and are major contributors to the viscoelastic properties of mucus secretion. For example, MUC5AC and MUC5B mucins are the predominant gel-forming glycoproteins in airway mucus (Thornton and Sheehan, 2004). The soluble mucin MUC7 is significantly smaller than the gel-forming mucins and has no recognizable domains in its extracellular region. It is most abundantly expressed in the less viscous secretions of salivary (Bobek et al., 1993) and lachrymal glands (Gipson, 2004).
Membrane mucins, including MUC1, MUC3A, MUC3B, MUC4, MUC11, MUC12, MUC13, MUC17, and MUC20 are defined by the presence of a single hydrophobic transmembrane domain that secures them to the cell surface. With the exception of MUC4, all membrane mucins contain a SEA (Sea urchin sperm protein, Enterokinase, and Agrin) domain in their extracellular regions that may be involved in binding carbohydrate moieties. Several of the membrane mucins also contain EGF-like domains that may be involved in protein–protein interactions. Membrane mucins are usually found at the apical surface of epithelial cells, providing protection to the epithelia. Membrane mucins can also be found as soluble molecules as a result of either splice removal of exons encoding the transmembrane and intracellular domains exons (Moniaux et al., 2000; Williams et al., 1999), or by proteolytic removal of the mucin from its transmembrane tether (Boshell et al., 1992; Wang et al., 2002). The soluble forms of membrane mucins can be found in fluids such as milk, tears, and saliva, or may remain loosely bound to the cell surfaces as part of the protective mucin barrier. While their functional roles remain to be fully elucidated, it is possible that soluble forms of membrane mucins could aid in the protection of epithelia from microbes. For example, it has been suggested that the presence of soluble membrane mucins in mothers' milk could provide the newborn with protection from enteric pathogens (Newburg et al., 2005; Ruvoen-Clouet et al., 2006).
B Membrane Mucins and Tumor Progression
Intense interest has developed in understanding the role of aberrantly expressed mucins in the genesis and progression of tumors. MUC1 is highly expressed in the vast majority (>90%) of human breast tumors, and mislocalization of MUC1 (nonapical localization) predicts poor patient outcome (Rakha et al., 2005). MUC1 is overexpressed and differentially glycosylated in a number of other human tumors as well, including pancreatic, gastrointestinal, and lung, where it is associated with metastatic and invasive potential and has been used as a diagnostic and prognostic factor (Taylor-Papadimitriou et al., 1999). Several assays to detect tumor-associated antigens in serum samples are based on antibodies directed against circulating MUC1 antigens (Baldus et al., 2004a), and are used in the postoperative monitoring of breast and ovarian carcinoma patients. MUC4 overexpression may also eventually serve as a diagnostic and prognostic marker for numerous cancers, including pancreatic tumors (Swartz et al., 2002), where its expression is associated with metastatic phenotype (Singh et al., 2004), lung adenocarcinomas (Llinares et al., 2004), and mass-forming type intrahepatic cholangiocarcinoma, where its coexpression with ErbB2 correlates with short survival time (Shibahara et al., 2004). MUC4 expression was shown to be increased during the pathologic process of squamous dysplastic transformation of exocervical epithelium, and could possibly be used as a marker in this process (Lopez-Ferrer et al., 2001).
Of the membrane mucins, human MUC1 and rat MUC4 have been studied in the greatest detail functionally and biochemically. Both are present at the cell surface as heterodimers formed from high molecular weight precursors, proteolytically cleaved early in their transit to the cell surface (Ligtenberg et al., 1992; Sheng et al., 1990). Both provide protection to the cell surface by virtue of their rigid and...
Erscheint lt. Verlag | 21.9.2011 |
---|---|
Mitarbeit |
Herausgeber (Serie): Gerald P. Schatten |
Sprache | englisch |
Themenwelt | Sachbuch/Ratgeber |
Naturwissenschaften ► Biologie ► Biochemie | |
Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie | |
Naturwissenschaften ► Biologie ► Zellbiologie | |
Technik | |
ISBN-10 | 0-08-047509-4 / 0080475094 |
ISBN-13 | 978-0-08-047509-7 / 9780080475097 |
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