Inhibitors of Cell Growth

The containment of cell growth is at the core of the homeostatic regulation of metazoans, and considerable progress has been made in the understanding of how this is achieved. Most knowledge comes from the isolation of molecu­ les with positive and negative regulatory effects on cell proliferation, and most emphasis so far has been on these molecules. Some of these molecules are already available for therapeutic purposes, and others look promising in this respect. This volume gives examples of such approaches. The understanding of the control of cell growth is also fundamental to grasp phylogenic and ontogenic development. Why organisms have developed increasingly sophisticated mechanisms that control their size and that of their organs, how different cells originate, some destined for renewal and repair, others for specialized functions in a postmitotic state or evolving through division, others like the germinal cells waiting for the signal to start another organism. There is one mechanism of growth containment, however, about which we know very little. It concerns the structural characteristics of the cell, i.e. the relationship between structure and function. How structure can change the response to identical signals. The positive and negative growth regulators may be conserved, but the structure and organization of the genetic material and of other cell components differ widely and are responsible to a great extent for the differences in cell proliferative behaviour.

Contenu

References.- The Growth-Inhibitory Effects of TGF?.- 1 Introduction.- 2 The Eukaryotic Cell Cycle.- 3 Effects of TGF? on Cell-Cycle Progression.- 3.1 TGF? Inhibition of CDK and Cyclin Expression.- 3.2 TGF? Effects on p15 Activity.- 3.3 TGF? Effects on p27 Activity and CDKI Distribution.- 4 Conclusions.- References.- Big Brothers Are Watching: the Retinoblastoma Family and Growth Control.- 1 Introduction.- 2 Interaction of Retinoblastoma Family Proteins with the Transcription Factor E2F.- 3 Structure and Expression of Retinoblastoma Family Members.- 4 Growth Inhibition by Retinoblastoma Family Members.- 5 Effects of Deletions of RB Family Members on Mice Development.- 6 Regulation of RB Family Members by Cyclin/CDK complexes - the Restriction Point.- 7 Role of pRB in Growth-Promoting Pathways.- 8 Role of pRB in Growth-Inhibiting Pathways; Apoptosis and Differentiation.- 8.1 pRB as a Downstream Effector of p53.- 8.2 RB Family Members in Differentiation.- 8.3 RB Family Members in TGF ?-Mediated Growth Inhibition.- 9 RB2/130 and p107 Confer a Growth Suppressive Ability, Other than pRB.- 10 pRB Inhibits Biosynthesis Via Inhibiting RNA pol I and pol III-Dependent Transcription.- 11 RB Family Members Interact with Several Other Growth-Regulating Genes.- 12 Concluding Remarks.- References.- The Growth-Regulatory Role of p21(WAF1/CIP1).- 1 Introduction.- 2 p21-Induced Growth Arrest Is Mediated Through Protein-Protein Interactions.- 2.1 p21 Promotes Cell-Cycle Arrest via Interactions with Cdks and PCNA.- 2.2 Proteins Other than Cdks and PCNA that Bind p21.- 2.3 Protein Interaction Domains of p21.- 3 p21 Expression During Development and Differentiation.- 4 Growth Suppression by p21.- 5 p21 Expression and Apoptosis.- 6 Regulation of p21 Expression.- 6.1 p53-Dependent Regulation of p21 Transcription.- 6.2 p53-Independent Activation of p21 Promoter.- 6.3 Repression of p21 Promoter Activity.- 7 p21 and Transcriptional Activation of Downstream Genes.- 8 p21 and Cancer.- References.- Mechanisms of Cell Cycle Blocks at the G2/M Transition and Their Role in Differentiation and Development.- 1 Introduction.- 2 Cdk Kinases and Cell-Cycle Control.- 3 Basic Controls of Cdc2 Kinase Activity.- 3.1 Positive Control of Cdc2 Kinase.- 3.2 Negative Control of Cdc2.- 3.2.1 Inhibitory Phosphorylations.- 3.2.2 Control of the Controllers.- 3.3 Negative Regulators of Cdc2.- 4 Mechanisms of Negative Control at G2/M.- 5 Oncogenes and Tumor-Suppressor Genes in G2 Arrest.- 6 G2/M Blocks in Meiosis.- 6.1 Oocyte Maturation.- 6.2 Release from Meiosis I.- 6.3 Control of Meiosis II.- 6.4 Mouse Oogenesis and Spermatogenesis.- 7 G2 Blocks During Development.- 7.1 String, Twine, and Drosophila Development.- 8 G2 Blocks in Differentiation.- 8.1 Polyploidy and Endoreduplication.- References.- Mechanisms of Interferon Action.- 1 Introduction.- 2 The Interferon Proteins and Genes.- 2.1 Classification and Biological Properties.- 2.2 Evolution of the IFN Genes.- 2.3 Tissue Distribution and Regulation of IFN Gene Expression.- 2.3.1 Type I IFN Genes.- 2.3.2 The IFN? Gene.- 3 The Interferon Receptors.- 3.1 The Cytokine Receptor Superfamily.- 3.2 The Type I IFN Receptor Complex.- 3.3 The Type II IFN Receptor Complex.- 4 IFN-Dependent Signaling Pathways.- 4.1 Identification of IFN-Dependent Signaling Factors.- 4.1.1 The JAKs.- 4.1.2 The STATs.- 4.2 Type II IFN Signaling.- 4.3 Type I IFN Signaling.- 4.4 Other IFN-Induced Signaling Components.- 5 IFN-stimulated Genes.- 5.1 Kinetics of ISG Induction.- 5.2 Mediators of Antiviral Responses.- 5.2.1 The 2,5-Oligoadenylate Synthetases.- 5.2.2 The Mx Proteins.- 5.2.3 The dsRNA-Induced Kinase PKR.- 5.2.4 IFN-Regulatory Factors.- 5.3 IFN Regulation of Cell-Cycle Components.- 6 Therapeutic Potentials of the IFNs.- 6.1 Cancers.- 6.2 Viral Diseases.- 6.3 Other Diseases.- 7 Interferons as Hormones of Pregnancy.- 8 Conclusion.- References.- Growth-Inhibiting N-Substituted Endogenous Peptides.- 1 Introduction.- 2 Purification and Characterization of Endogenous Growth Inhibitors.- 2.1 Early Attempts at Purification.- 2.2 Structure and Biological Properties of Endogenous Bone Marrow Growth-Inhibiting Peptides.- 2.3 Structure and Biological Properties of the Inhibitory Epidermal Pentapeptide.- 3 Other N-Substituted Inhibitory Oligopeptides.- 3.1 Inhibitory Oligopeptides in Liver, Colon, and Melanocytes.- 3.2 Inhibitory N-Substituted Oligopeptides Not Related to Specific Organs/Tissues.- 4 N-Substituted Inhibitory Oligopeptides in Neoplasia.- 4.1 Carcinogenesis.- 4.2 N-Substituted Inhibitory Oligopeptides and Tumors.- 5 Purification Procedures Used for Characterization of N-Substituted Peptides.- 5.1 Extraction and Chromatography Systems.- 5.2 Biochemical Characterization of Peptides.- 5.3 Criteria for Purity.- 5.4 Criteria for Identity Between Native and Synthetic Peptides.- 6 "Chalones" and Inhibitory N-Substituted Oligopeptides: Similarities and Differences.- 7 Possible Strategies for Clinical Use of Endogenous Growth Inhibitors.- 7.1 Possible Use of Endogenous Inhibitors in Medicine.- 7.2 Possible Use of Stimulating Dimers and Peptidomimetics.- 8 Concluding Remarks.- References.- Endogenous Angiogenesis Inhibitors: Angiostatin, Endostatin, and Other Proteolytic Fragments.- 1 Introduction.- 2 Angiostatin.- 2.1 Discovery.- 2.2 Structure and Generation.- 2.3 Antiendothelial, Antiangiogenic and Antitumor Effects.- 2.4 Kringle 5.- 3 Endostatin.- 3.1 Structure.- 3.2 Antiangiogenic and Antitumor Activities.- 4 Other Angiogenesis Inhibitors.- 4.1 Endogenous Inhibitors.- 4.2 Proteolytic Fragments.- 4.3 Small Peptides.- 5 Clinical Applications.- References.- Inhibitors of Preadipocyte Replication: Opportunities for the Treatment of Obesity.- 1 Introduction.- 2 Preadipocytes.- 3 Relationship Between Host Characteristics and Adipose Cell Dynamics.- 4 Control of Preadipocyte Replication.- 5 Potential Therapeutic Strategies.- References.- Growth Inhibitors for Mammary Epithelial Cells.- 1 Introduction.- 2 The Role of Transforming Growth Factor-? (TGF-?) in Mammary Gland Development.- 2.1 TGF-? Is a Multifunctional Factor of Normal Mammary Gland Development.- 2.1.1 TGF-?-Can Act Exogenously on Mammary Development in Vivo.- 2.1.2 Evidence for Endogenous TGF-? in the Mammary Gland.- 2.1.3 In Vitro Studies for TGF-? Activity.- 2.2 TGF-? Is a Growth Inhibitor Modulating Differentiation of the Mammary Gland.- 2.2.1 TGF-?s Role in Mammary Gland Tumorigenesis.- 2.2.2 Alterations in TGF-? Production.- 2.…