Book Review

Handbook of Growth Factors: General basic aspects

Handbook of Growth Factors: Peptide growth factors

Handbook of Growth Factors: Hematopoietic growth factors and cytokines

N Engl J Med 1995; 332:896-897March 30, 1995

Article

Handbook of Growth Factors: General basic aspects
(Vol. I.) By Enrique Pimentel. 370 pp. Boca Raton, Fla., CRC Press, 1994. $85. ISBN: 0-8493-2505-6

Handbook of Growth Factors: Peptide growth factors
(Vol. II.) By Enrique Pimentel. 362 pp. Boca Raton, Fla., CRC Press, 1994. $85. ISBN: 0-8493-2506-4

Handbook of Growth Factors: Hematopoietic growth factors and cytokines
(Vol. III.) By Enrique Pimentel. 370 pp. Boca Raton, Fla., CRC Press, 1994. $85. ISBN: 0-8493-2507-2

This three-volume set, unassumingly entitled Handbook of Growth Factors, is in fact an encyclopedic review of the entire field of mitogens and signaling pathways. The books are comprehensive, detailed, and well written and, in my opinion, will serve as valuable references for investigators working in the field of growth factors.

On reading through these books I found little to criticize beyond the inevitable failure to cite the absolutely latest material. The most obvious of these deficiencies are commented on below. Most chapters cite references up to 1993.

The first volume, General Basic Aspects, deals with the general principles of cell proliferation and differentiation. It begins with a chapter on the cell cycle and its regulation by cyclins and cyclin-dependent kinases. The material is current except for the lack of information on cyclin inhibitors such as the p53-induced WAF-1 and the p16 melanoma-susceptibility gene products, both of which have been shown to serve as brakes on the cell cycle. This chapter also includes material on apoptosis and the role played by bcl-2 in the suppression of the process but does not mention the other members of the bcl-2 family that dimerize with bcl-2 or the association of bcl-2 with various ras-related proteins, all of which affect the function of the bcl-2 molecule.

Most of the subsequent chapters deal with various secondary messengers shared by diverse signaling pathways activated by the cytokines discussed in detail in the second and third volumes of the set. The first volume includes, for example, an entire chapter on the cyclic nucleotides and their effects on various kinases and transcription factors. This is followed by a comprehensive chapter on G proteins, approximately 75 percent of which is focused on the ras superfamily. Although it discusses the activation of ras by nucleotide exchange factors and its suppression by various guanosine triphosphatase–activating proteins including neurofibromin, this chapter is otherwise somewhat dated in that it mentions neither the role of ras in the membrane localization of raf nor the signaling cascade from ras to mitogen-activated protein (MAP) kinases.

The chapter on protein kinases is perhaps the least satisfactory in this volume because it omits several recently described kinases, notably the members of the syk and Janus kinase family. The latter participate in the signaling pathways of nearly all the hematopoietic cytokines reviewed in the third volume of the set. The material on the src family is also somewhat dated. The T-cell–specific member pp56^lck, for example, is not mentioned as the critical kinase involved in the phosphorylation of the T-cell–antigen receptor zeta chain, a protein critically involved in T-cell activation.

The second volume, entitled Peptide Growth Factors, deals with mitogens known primarily for their effects on cells other than those of the immune or hematopoietic system. With the notable exception of platelet-derived growth factor, which is only briefly mentioned, virtually all the fibroblast and endothelial-cell growth factors are thoroughly discussed. This volume includes separate chapters on insulin, the insulin-like growth factors, the fibroblast-growth-factor and epidermal-growth-factor (EGF) families, the transforming growth factors (TGFs), and the neurotrophins. Angiogenic factors such as vascular endothelial growth factor and hepatocyte growth factor, neuroendocrine peptides such as bombesin and vasoactive intestinal peptide, and vasoactive peptides, including endothelin and angiotensin, are also discussed.

Each chapter reviews the biologic effects of the pertinent cytokines and includes material on the biochemistry of the cytokine family, its receptors, and signaling pathways. With few exceptions, this material is remarkably current. For example, the chapter on the EGF family discusses the role of the EGF-related proteins c-neu/erb-B2 and erb-B3 in the development and propagation of cancers such as breast cancer. The section on EGF-receptor signaling includes data on the adaptor protein grb2 and the nucleotide exchange factor sos, proteins recently shown to translocate to the membrane in response to ligand-induced receptor dimerization and to activate the ras signaling pathway.

By contrast, the section on TGFs only briefly mentions the bone morphogenetic proteins, a rapidly enlarging family of TGF-related proteins involved in bone mineralization. Likewise, the chapter on insulin does not mention the cloning of a ribosomal protein PHAS-I that binds to eIF and suppresses protein synthesis unless phosphorylated by an insulin-activated kinase. This recently elucidated pathway may account for the enhanced protein synthesis induced by insulin and other growth factors.

The third volume of the set, Hematopoietic Growth Factors and Cytokines, includes an introductory chapter on hematopoiesis, followed by chapters on the interleukins (up to interleukin-13), colony-stimulating factors (CSFs), interferons, tumor necrosis factors (TNFs), and other cytokines that regulate hematopoietic stem-cell proliferation and differentiation. As was the case in volume II, each chapter discusses in detail the biochemistry of the pertinent cytokines, their receptors, and the intracellular signaling pathways activated by ligand engagement. The known physiologic effects of each cytokine are also reviewed.

Generally speaking, this material is reasonably up to date. The chapter on CSFs, for example, briefly alludes to the existence of a factor (thrombopoietin) present in thrombocytopenic serum that is capable of stimulating platelet production. The cloning and biochemical characterization of thrombopoietin were just reported last year. The chapter on TNFs discusses recent findings regarding the role of sphingomyelin and ceramide-activated protein kinases in TNF signal transduction. Similarly, the recent observation that the multimeric receptors of distinct cytokines (such as interleukin-3, interleukin-5, and granulocyte–macrophage CSF) share receptor subunits is reviewed.

However, this volume does not cite other important observations and concepts prominently featured in the current literature. For example, the interleukin-1–converting enzyme is not mentioned in the section on interleukin-1. This cysteine protease, which is responsible for the processing of interleukin-1β from an inert precursor into an active cytokine, has recently been shown to be structurally related to a helminth protein intimately involved in the regulation of programmed cell death (apoptosis). The material on the interleukin-1–receptor antagonist, confined to one brief paragraph, does not cite any of the literature on the successful use of this immune modulator to suppress inflammation in animal models or to reduce mortality due to sepsis.

The section on interleukin-2 gene expression has an elaborate description of the components of the T-cell–antigen receptor but makes no mention of the interaction between B7 and CD28 in the costimulation of T cells. The interleukin-2 receptor is discussed as a mere heterodimer without reference to the recently cloned third (gamma) chain. The gamma chain has recently been demonstrated to represent a critical component of several hematopoietin receptors. Mutations in the gamma-chain gene account for X-linked severe combined immunodeficiency disorder in humans. There is no mention of the Janus family of protein kinases or the STAT proteins, which have been shown to be involved in signal transduction and the activation of transcription in response to nearly all cytokines studied to date. Finally, the ability of interleukin-12 to bias helper T-cell differentiation in the direction of the TH1 phenotype is not mentioned. This is arguably the most important of the physiologic functions attributed to this cytokine.

The field of cytokine biology is evolving rapidly, and the preparation of an inclusive, up-to-date review of current research topics would be problematic for even a team of authors. That this could be accomplished by a single investigator is remarkable. Dr. Pimentel is to be congratulated on this excellent contribution to the field.

James W. Mier, M.D.
New England Medical Center, Boston, MA 02111