- Email: [email protected]
Programmed cell death in tumours and tissues
TIBS 16-FEBRUARY1991
inability to predict the folding pathway and final structure of a protein sequence is a fundamental gap in theoretical biology. It also frustrates the practical benefits that would follow the capacity to design protein molecules de novo. Protein Folding addresses the present state of research into folding. It is composed of articles that were originally presented in an obviously successful symposium devoted to folding; thus it has a good degree of coherence. There are sections dealing extensively with protein structure and interactions ( including those with wateO, with folding pathways and intermediates, with modelling and with design. The importance of protein and recombinant protein folding are also recognized and given their own sections. Readers of the book will get a vivid impression of the diversity of systems under study and of the impressive variety of techniques employed in folding research. In spite of the complexity of the problem, the articles are optimistic. The optimism stems from the feeling that there is real progress being made in describing the character of the process and in identifying some of its crucial stages. This progress is coming first from site-directed mutagenesis experiments. Second, from the remarkable growth in the knowledge of protein's threedimensional structure obtained through X-ray analysis and NMR spectroscopy. Third, there are the specific binding properties of monocional antibodies, which are being used to detect the existence of partial structures very successfully. Finally, the advent of formidable computing power and the
Exploration into the realm of cell death ProgrammedCell Death in Tumours and Tissues by Ivor D. Bowenand Sandra Maureen Bowen, Chapmanand Hall, 1990. £38.00 (i + 268 pages) ISBN 0 412 27970 3 The mechanisms underlying cell division have been actively investigated for maay years, and the insights gained have led to a better understanding of tissue homeostasis and the events that lead to cancer. Cell death occurring normally or as the result of environmental assault is also an important part of life, although fewer investigations have devoted their efforts to understanding the mechanisms involved. This is especially true for cases of cell death that are not accidental.
increasingly appropriate methods of molecular calculation are making it possible to analyse and simulate the folding processes themselves. The evidence presented in th~.~book makes a convincing general picture in which the unfolded and folded states exist in a two-state equilibrium, and in which the transition from the unfolded to the folded state is a cooperative process involving transient structures. These are not altogether new concepts, they were formulated, particularly by Anfinsen, 20 years ago. What are new are, for example, the spectroscopic observations that indicate that even very small peptides can have definite structures in solution and the crystallographic studies which have revealed them in atomic detail. These approaches have given experimental validity to the scheme in which transient local structure in a protein can create a platform on which new elements of structure are stabilized, in turn stabilizing further structure in a cooperative progress to the completely folded molecule. Also new is the use of site-directed mutants, which are opening the way to defining the contributions of individual amino acids to the folded and intermediate states, and bringing structural and thermodynamic detail at last into our understanding of the process. The difficulty with a volume like this is that each article tends to carry its own introduction and its own statements of philosophy, which made some of the reading feel repetitive. In addition, any collection of technical articles concentrating on particular experiments
Programmed cell death (apoptosis) is a process of physiological cell deletion that occurs during normal cell turnover, hormone-induced tissue atrophy, cellmediated immune cytolysis and tumour regression. It can be readily distinguished from 'random' cell death (necrosis) by many morpholo~cal and biochemical criteria; most notably, apoptosis appears to be genetically controlled. Increasing evidence suggests that apoptosis plays a critical role in the development of the immune and central nervous systems. Other exciting recent work has shown that certain agents with anti-tumour activity induce apoptosis in their targets, a property that hopefully can be exploited in future cancer therapy. In light of these observations, investigators are finally becoming interested in programmed cell death, although the concept itself has been around for decades. In contrast to those of us who have entered the realm during the surge of interest within the last several years, the authors of Programmed
or systems makes for some fairly difficult reading. Although the collection of articles broadly covers the field, there is no account of the fast-mixing techniques, •,vh,ch can be coupled with H-exchange and NMR analysis, though there is reference to them. This combination of methods, applied by Udgaonkar and Baldwin [Nature (1988) 335, 694] and Roder, Elove and Englander [Nature (1988) 335, 700], have demonstrated the existence and interactions of folding intermediates very nicely. And since these articles were written there have inevitably been further important advances. For example, Fersht and colleagues reported their use of protein engineering to characterize folding intermediates and their interactions and, most importantly, to derive their energetics [Nature (1990) 346, 440 and 488]. Thus the prospects for describing the folding process are excellent; however, the step from the experimental descriptions to predicting threedimensional structure for a sequence are still very distant. In conclusion, a good proportion of the articles are first rate and the overall organization of the book is well judged. I liked the linking of the different sections by brief overviews, which will help readers new to the field. ! can recommend the book to all wanting an up-to-date account of a most important field.
GUY DODSON Universityof York, Departmentof Chemistry, YorkY015DD, UK.
Cell Death in Turnouts and Tissues have been actively involved in research on apoptosis since the field's beginnings. Thei~ perspective makes this volume a welcome addition to the available literature on the subject. The strengths of this book lie in its exhaustive review of the literature (spanning three decades) and its solid presentation of those morphological and biochemical features of programmed cell death that distinguish it from necrosis. The authors detail what is known of the regulation of the process, including roles for genetic and second messenger (calcium) control. A large portion of the work is devoted to a presentation of current views on the potential antitumour actions of relevant cytokines and immune effector cells that likely involve apoptosis. A convenient appendix, containing des:~::pLions of selected techniques utilized by the authors in their own work, concludes the work. I generally found the text to be quite comprehensive and well presented. The 77
TIB$16-FEBRUARY1991
histological and morphological information discussed was solid and scholarly. ! was less satisfied with the arguments for genetic control of apoptosis, although this part of the field is truly in its infancy and the attempt is therefore commendable. My only strong criticisms of the work are concerned with several topics that I felt were only briefly discussed, if at all. These include the concept of growth factor withdrawal and the biochemical changes occurring at the cell surface (including transglutaminase
activation), which may be relevant to cell containmev~, and subsequent recognition by tissue macrophages. I would also have liked to see a more dezailed account of the possible relationship between cell division and apoptosis, especially because increasing evidence suggests that shared receptors and signalling processes are involved in both. These details aside, I fouad the book to be well worth owning. I would especially recommend it to those less familiar with the historical development and basic
concepts of programmed cell death. The space devoted to interleukins, cytokines and immune effector cells will be of interest to immunologists and oncolog;,sts alike. The volume will no doubt win over even more enthusiastic supporters of this important biological concept.
Fun and more fun with red cells
chapters on glycophorin structure, its gene structure and associations with phosphoinositides. Also, the ultrastructure and function of the cytoskeleton and the dynamic aspects of structure are described in articles on the red cell shape, membrane protein and lipid diffusion and the rheological properties of the cell. Little emphasis is given to structural aspects of the red cell in Raess and Tunnicliff. The main thrust of this book is given to accounts of solute transport across the cell membrane- which are as detailed, but more concise than in Agre and Parker. The thread correlating structure and function in Agre and Parker is continued with the Na-K ATPase (Mercer, Schneider and Benz) paired with a chapter on active transport of Na and K (Kaplan); the same ground is covered in Raess and Tunnicliff. Similarly, the catalytic mechanisms of the Ca pump (Rega and Garrahan) Is paired with an article on its regulation (Vincenzi) in Raess and Tunnicliff, whereas Vincenzl covers the lot in Agre and Parker. There are excellent articles on the structure and function of the anion transporter (Jennings) and an unbiased account of one- and two-site kinetics models of anion exchange in Agre and Parker. These are matched in Agre and Parker by articles on band3 interactions with native and denatured haemoglobins (Low) and anion transport (Gunn and colleagues). There is a well constructed article on the structure of the sugar transporter (Mueckler) and sugar transport is given a one-site spin (Lowe and Walmsley) in Agre and Parker, whereas in Raess and Tunnicliff, Carruthers examines the pros and cons of both one- and two-site sugar transport kinetics. Additionally, there are parallel treatments of passive Na-dependent systems by Parker and Dunham (Agre and Parker) and by Stewart and Ellory (Raess and Tunnicliff). Both articles discuss the quasi-stoichiometric relationships of the Na, K, CI electroneutral cotransport system in different red cell transport systems. There are also excellent articles on the tran~ferrin receptor (Johnstone),
nucleoside transport (Gati and Paterson) and regulated transport (Haas) in Agre and Parker, which are without any analogue. However, Raess and Tunnicliff have an article on amino acid transport (Tunnicliff), a pharmacology section on the Ca pump, alterations of the anion transporter and action of Ca on K flux, plus Ca fluxes in pathological cells. There is a shorter section on transport disorders (Berkowitz and Griffin) and structural disorders in red cells (Agre) in Agre and Parker. Both books are uniformly well written compendia, with good illustrations and adequate indices. I enjoyed particularly the articles by Jennings and Knauf on anion transport, the article by Stewart and Ellory on chloride-dependent cation transport, the chapter on modelling of cell volume by Lew et aL and that by Carruthers on sugar transport in Raess and Tunnicllff, because they were cogent, critical and, above all, thought provoking. In Agre and Parker, the articles that I found of similar Interest were those by Kaplan, Parker and Dunham and Haas, Surprising omissions from both books were accounts of water transport and effects of parasitic infection on red cell transport. While both books attempt to bridge the gulf in understanding between transporter structure and function, a synthesis in any one topic is still over the horizon- even with the sugar transporters that have been sequenced and about which there is extensive kinetic information, there is no unambiguous picture. The number of binding sites, or their position and any understanding of the conformational changes taking place during transport, is still a matter of speculation. Clearly there is a need for further studies on solute-induced conformational changes and transport properties in mutated transport systems before answers to these questions can be provided - so we can look forward to lots more fun with red cells.
Red BloodCell Membranes:Structure,
Function. Clinical Implications edited by Peter Agre and John C. Parker, Marcel Dekker, 1989. $150.00 (USA and Canada) $180.00 (all other countries) (xx + 733 pages) ISBN 0 824 7 8022 1
The Red Cell Membrane:A Model for
Solute Transport edited by B. U. Raess and G. T~Mcliff, The Humana Press, 1990. :[.83.85 (xx + 475 pages) ISBN 0 89603 158 6 'Despite a heyday of research spanning two decades, the red cell membrane continues to provide new avenues of inquiry', claim Agre and Parker in defense of their book, which swells the already bloated literature on red cell transport. Are two more books in this genre required? Both are multi-authored reviews with similar aims and are addressed to an audience of transport physiologists and biochemists, cell biologists and haematologists. Both attempt to provide a synthesis between structural and kinetic studies of red cell research and for this reason there are areas of overlap. Nevertheless, despite the obvious temptation to discriminate between the alternative versions on Na-pump structure and function, passive Na transport, C! transport and sugar transport, ! find that the books are in many ways complementary. In Agre and Parker, the structural and functional aspects of the red cell cytoskeleton are given considerable emphasis, with articles on interactions between membrane skeletal proteins, the molecular biology of the red cell skeleton, its changes during erythroid differentiation and its abnormal d~.velopment. There are separate
78
DAVID J. McCONKEY Daner-FarberCancerInstitute, Laboratoryof Immunobiology,44 BinneySt, Boston,MA02115, USA.
RICHARD NAFTAL-IN Departmentof Physiology,King'sCollegeLondon, The Strand,LondonWC2R2LS, UK. 4
inability to predict the folding pathway and final structure of a protein sequence is a fundamental gap in theoretical biology. It also frustrates the practical benefits that would follow the capacity to design protein molecules de novo. Protein Folding addresses the present state of research into folding. It is composed of articles that were originally presented in an obviously successful symposium devoted to folding; thus it has a good degree of coherence. There are sections dealing extensively with protein structure and interactions ( including those with wateO, with folding pathways and intermediates, with modelling and with design. The importance of protein and recombinant protein folding are also recognized and given their own sections. Readers of the book will get a vivid impression of the diversity of systems under study and of the impressive variety of techniques employed in folding research. In spite of the complexity of the problem, the articles are optimistic. The optimism stems from the feeling that there is real progress being made in describing the character of the process and in identifying some of its crucial stages. This progress is coming first from site-directed mutagenesis experiments. Second, from the remarkable growth in the knowledge of protein's threedimensional structure obtained through X-ray analysis and NMR spectroscopy. Third, there are the specific binding properties of monocional antibodies, which are being used to detect the existence of partial structures very successfully. Finally, the advent of formidable computing power and the
Exploration into the realm of cell death ProgrammedCell Death in Tumours and Tissues by Ivor D. Bowenand Sandra Maureen Bowen, Chapmanand Hall, 1990. £38.00 (i + 268 pages) ISBN 0 412 27970 3 The mechanisms underlying cell division have been actively investigated for maay years, and the insights gained have led to a better understanding of tissue homeostasis and the events that lead to cancer. Cell death occurring normally or as the result of environmental assault is also an important part of life, although fewer investigations have devoted their efforts to understanding the mechanisms involved. This is especially true for cases of cell death that are not accidental.
increasingly appropriate methods of molecular calculation are making it possible to analyse and simulate the folding processes themselves. The evidence presented in th~.~book makes a convincing general picture in which the unfolded and folded states exist in a two-state equilibrium, and in which the transition from the unfolded to the folded state is a cooperative process involving transient structures. These are not altogether new concepts, they were formulated, particularly by Anfinsen, 20 years ago. What are new are, for example, the spectroscopic observations that indicate that even very small peptides can have definite structures in solution and the crystallographic studies which have revealed them in atomic detail. These approaches have given experimental validity to the scheme in which transient local structure in a protein can create a platform on which new elements of structure are stabilized, in turn stabilizing further structure in a cooperative progress to the completely folded molecule. Also new is the use of site-directed mutants, which are opening the way to defining the contributions of individual amino acids to the folded and intermediate states, and bringing structural and thermodynamic detail at last into our understanding of the process. The difficulty with a volume like this is that each article tends to carry its own introduction and its own statements of philosophy, which made some of the reading feel repetitive. In addition, any collection of technical articles concentrating on particular experiments
Programmed cell death (apoptosis) is a process of physiological cell deletion that occurs during normal cell turnover, hormone-induced tissue atrophy, cellmediated immune cytolysis and tumour regression. It can be readily distinguished from 'random' cell death (necrosis) by many morpholo~cal and biochemical criteria; most notably, apoptosis appears to be genetically controlled. Increasing evidence suggests that apoptosis plays a critical role in the development of the immune and central nervous systems. Other exciting recent work has shown that certain agents with anti-tumour activity induce apoptosis in their targets, a property that hopefully can be exploited in future cancer therapy. In light of these observations, investigators are finally becoming interested in programmed cell death, although the concept itself has been around for decades. In contrast to those of us who have entered the realm during the surge of interest within the last several years, the authors of Programmed
or systems makes for some fairly difficult reading. Although the collection of articles broadly covers the field, there is no account of the fast-mixing techniques, •,vh,ch can be coupled with H-exchange and NMR analysis, though there is reference to them. This combination of methods, applied by Udgaonkar and Baldwin [Nature (1988) 335, 694] and Roder, Elove and Englander [Nature (1988) 335, 700], have demonstrated the existence and interactions of folding intermediates very nicely. And since these articles were written there have inevitably been further important advances. For example, Fersht and colleagues reported their use of protein engineering to characterize folding intermediates and their interactions and, most importantly, to derive their energetics [Nature (1990) 346, 440 and 488]. Thus the prospects for describing the folding process are excellent; however, the step from the experimental descriptions to predicting threedimensional structure for a sequence are still very distant. In conclusion, a good proportion of the articles are first rate and the overall organization of the book is well judged. I liked the linking of the different sections by brief overviews, which will help readers new to the field. ! can recommend the book to all wanting an up-to-date account of a most important field.
GUY DODSON Universityof York, Departmentof Chemistry, YorkY015DD, UK.
Cell Death in Turnouts and Tissues have been actively involved in research on apoptosis since the field's beginnings. Thei~ perspective makes this volume a welcome addition to the available literature on the subject. The strengths of this book lie in its exhaustive review of the literature (spanning three decades) and its solid presentation of those morphological and biochemical features of programmed cell death that distinguish it from necrosis. The authors detail what is known of the regulation of the process, including roles for genetic and second messenger (calcium) control. A large portion of the work is devoted to a presentation of current views on the potential antitumour actions of relevant cytokines and immune effector cells that likely involve apoptosis. A convenient appendix, containing des:~::pLions of selected techniques utilized by the authors in their own work, concludes the work. I generally found the text to be quite comprehensive and well presented. The 77
TIB$16-FEBRUARY1991
histological and morphological information discussed was solid and scholarly. ! was less satisfied with the arguments for genetic control of apoptosis, although this part of the field is truly in its infancy and the attempt is therefore commendable. My only strong criticisms of the work are concerned with several topics that I felt were only briefly discussed, if at all. These include the concept of growth factor withdrawal and the biochemical changes occurring at the cell surface (including transglutaminase
activation), which may be relevant to cell containmev~, and subsequent recognition by tissue macrophages. I would also have liked to see a more dezailed account of the possible relationship between cell division and apoptosis, especially because increasing evidence suggests that shared receptors and signalling processes are involved in both. These details aside, I fouad the book to be well worth owning. I would especially recommend it to those less familiar with the historical development and basic
concepts of programmed cell death. The space devoted to interleukins, cytokines and immune effector cells will be of interest to immunologists and oncolog;,sts alike. The volume will no doubt win over even more enthusiastic supporters of this important biological concept.
Fun and more fun with red cells
chapters on glycophorin structure, its gene structure and associations with phosphoinositides. Also, the ultrastructure and function of the cytoskeleton and the dynamic aspects of structure are described in articles on the red cell shape, membrane protein and lipid diffusion and the rheological properties of the cell. Little emphasis is given to structural aspects of the red cell in Raess and Tunnicliff. The main thrust of this book is given to accounts of solute transport across the cell membrane- which are as detailed, but more concise than in Agre and Parker. The thread correlating structure and function in Agre and Parker is continued with the Na-K ATPase (Mercer, Schneider and Benz) paired with a chapter on active transport of Na and K (Kaplan); the same ground is covered in Raess and Tunnicliff. Similarly, the catalytic mechanisms of the Ca pump (Rega and Garrahan) Is paired with an article on its regulation (Vincenzi) in Raess and Tunnicliff, whereas Vincenzl covers the lot in Agre and Parker. There are excellent articles on the structure and function of the anion transporter (Jennings) and an unbiased account of one- and two-site kinetics models of anion exchange in Agre and Parker. These are matched in Agre and Parker by articles on band3 interactions with native and denatured haemoglobins (Low) and anion transport (Gunn and colleagues). There is a well constructed article on the structure of the sugar transporter (Mueckler) and sugar transport is given a one-site spin (Lowe and Walmsley) in Agre and Parker, whereas in Raess and Tunnicliff, Carruthers examines the pros and cons of both one- and two-site sugar transport kinetics. Additionally, there are parallel treatments of passive Na-dependent systems by Parker and Dunham (Agre and Parker) and by Stewart and Ellory (Raess and Tunnicliff). Both articles discuss the quasi-stoichiometric relationships of the Na, K, CI electroneutral cotransport system in different red cell transport systems. There are also excellent articles on the tran~ferrin receptor (Johnstone),
nucleoside transport (Gati and Paterson) and regulated transport (Haas) in Agre and Parker, which are without any analogue. However, Raess and Tunnicliff have an article on amino acid transport (Tunnicliff), a pharmacology section on the Ca pump, alterations of the anion transporter and action of Ca on K flux, plus Ca fluxes in pathological cells. There is a shorter section on transport disorders (Berkowitz and Griffin) and structural disorders in red cells (Agre) in Agre and Parker. Both books are uniformly well written compendia, with good illustrations and adequate indices. I enjoyed particularly the articles by Jennings and Knauf on anion transport, the article by Stewart and Ellory on chloride-dependent cation transport, the chapter on modelling of cell volume by Lew et aL and that by Carruthers on sugar transport in Raess and Tunnicllff, because they were cogent, critical and, above all, thought provoking. In Agre and Parker, the articles that I found of similar Interest were those by Kaplan, Parker and Dunham and Haas, Surprising omissions from both books were accounts of water transport and effects of parasitic infection on red cell transport. While both books attempt to bridge the gulf in understanding between transporter structure and function, a synthesis in any one topic is still over the horizon- even with the sugar transporters that have been sequenced and about which there is extensive kinetic information, there is no unambiguous picture. The number of binding sites, or their position and any understanding of the conformational changes taking place during transport, is still a matter of speculation. Clearly there is a need for further studies on solute-induced conformational changes and transport properties in mutated transport systems before answers to these questions can be provided - so we can look forward to lots more fun with red cells.
Red BloodCell Membranes:Structure,
Function. Clinical Implications edited by Peter Agre and John C. Parker, Marcel Dekker, 1989. $150.00 (USA and Canada) $180.00 (all other countries) (xx + 733 pages) ISBN 0 824 7 8022 1
The Red Cell Membrane:A Model for
Solute Transport edited by B. U. Raess and G. T~Mcliff, The Humana Press, 1990. :[.83.85 (xx + 475 pages) ISBN 0 89603 158 6 'Despite a heyday of research spanning two decades, the red cell membrane continues to provide new avenues of inquiry', claim Agre and Parker in defense of their book, which swells the already bloated literature on red cell transport. Are two more books in this genre required? Both are multi-authored reviews with similar aims and are addressed to an audience of transport physiologists and biochemists, cell biologists and haematologists. Both attempt to provide a synthesis between structural and kinetic studies of red cell research and for this reason there are areas of overlap. Nevertheless, despite the obvious temptation to discriminate between the alternative versions on Na-pump structure and function, passive Na transport, C! transport and sugar transport, ! find that the books are in many ways complementary. In Agre and Parker, the structural and functional aspects of the red cell cytoskeleton are given considerable emphasis, with articles on interactions between membrane skeletal proteins, the molecular biology of the red cell skeleton, its changes during erythroid differentiation and its abnormal d~.velopment. There are separate
78
DAVID J. McCONKEY Daner-FarberCancerInstitute, Laboratoryof Immunobiology,44 BinneySt, Boston,MA02115, USA.
RICHARD NAFTAL-IN Departmentof Physiology,King'sCollegeLondon, The Strand,LondonWC2R2LS, UK. 4