Advances in Genetics increases its focus on modern human genetics and its relation to medicine with the merger of this long-standing serial with Molecular Genetic Medicine. This merger affirms theAcademic Press commitment to publish important reviews of the broadest interest to geneticists and their colleagues in affiliated disciplines.
Front Cover 1
Advances in Genetics, Volume 36 4
Copyright Page 5
Contents 6
Contributors 8
Chapter 1. The Peripheral Neuropathies and Their Molecular Genetics 10
I. Historical Introduction 11
II. Clinical Classification of CMT 11
III. Genetic Classification 13
IV. Molecular Mechanisms in CMT1A 17
V. Molecular Mechanisms of CMT1B, DSD, and CMTX1 28
VI. Myelin Proteins and Their Functional Significance 30
VII. Molecular Diagnostic Testing for CMT and HNPP 43
References 45
Chapter 2. Tumor Suppressor Genes and Human Cancer 54
I. Introduction 55
II. Tumor Suppressor Genes and Their Products 62
III. The Role of Tumor Suppressor Genes in Human Cancer 103
IV. Conclusions 114
References 116
Chapter 3. Genetic Redundancy 146
I. Introduction: The Evolutionary Background of Adaptation and Pleiotropy 147
II. Evidence for Redundancy 148
III. Apparent and True Redundancy 152
IV. The Organism and the Cell 159
V. Redundancy as a Fail-Safe System 160
VI. Functional Redundancy 161
VII. Conclusions 162
References 162
Chapter 4. Genetics of Hybrid Inviability in Drosophila 166
I. Introduction 166
II. Genetic Studies on Hybrid Inviability 168
III. Chromosomes and Genes Influencing Hybrid Viability 177
IV. Genetic Models for the Basis of Hybrid Inviability 184
V. Conclusions 188
References 190
Chapter 5. Regulation of Bacterial Gene Expression by Metals 196
I. Introduction 196
II. Essential Metals 199
III. Toxic Metals 214
IV. Concluding Remarks 235
References 236
Chapter 6. Chromosome Rearrangements in Neurospora and Other Filamentous Fungi 248
I. Introduction 250
II. General Information Regarding Neurospora Rearrangements 254
III. New Findings 265
IV. Rearrangements in Other Fungi 286
V. Individual Chromosome Rearrangements of Neurospora crassa 294
VI. Summary 391
References 392
Index 408
Tumor Suppressor Genes and Human Cancer
Melissa A. Brown Somatic Cell Genetics Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, England
I INTRODUCTION
Ideas contributing to our understanding of tumorigenic mechanisms date from the 1700s, when early records of cancer families suggested that cancer was a genetic disease. Most of our present knowledge, however, is built on the contributions of researchers in this century (reviewed in Witkowski, 1990). In 1911 Peyton Rous demonstrated that cell-free extracts from chickens could transmit tumors, suggesting the existence of tumor viruses. Subsequent studies on these viruses ultimately led to identification of the first dominantly acting oncogene, src, in 1976. The notion that abnormalities in chromosomes may cause cancer, suggested by Boveri in 1914, together with observations in the 1960s and 1970s that tumorigenicity could be suppressed by fusing malignant cells with either normal cells or specific chromosomes, led to the hypothesis that loss of genetic material may also be a critical event in tumorigenesis. This was later confirmed cytogenetically in 1983, subsequently leading to the isolation of the first tumor suppressor gene, RB, in 1986. Intensive research over the last 20 years has culminated in the isolation and characterization of over 50 dominantly acting oncogenes and the realization that the products of these genes are involved in the regulation of normal cell growth and development; the identification and isolation of many tumor suppressor genes, the products of which have been shown to be negative regulators of cell growth and development; and the demonstration that tumorigenesis is a multistep process requiring mutations in at least two of these cancer genes (reviewed in Fearon and Vogelstein, 1990; Vogelstein and Kinzler, 1993).
It has been only a decade since the isolation of the first tumor suppressor gene, yet a phenomenal amount of information has been generated in this area. Several themes have emerged. Tumor suppressor genes encode a diverse group of proteins which, through a variety of mechanisms, function to negatively regulate cell growth and development (Table 2.1). Perhaps due to the intensive interest in the factors controlling the cell cycle, many of the tumor suppressors isolated so far are directly involved in regulating this process, commonly binding and blocking the function of cyclin-dependent kinases (CDKs) (Fig. 2.1; Table 2.1). The importance of tumor suppressors in the control of other pathways has also been demonstrated: for example, upstream signal transduction pathways in the case of NF1; cell–cell communication in the case of DCC and possibly APC, and the mechanics of transcription in the case of VHL (Table 2.1).
Table 2.1
Characteristics of Tumor Suppressor Genes
| RB | pRb | 13q14 | Negative regulator of E2F transcription factors | Familial retino-blastoma | Yes | Yes | Disruptive (deletion, loss of expr.) | Varies | Yes | Yes | Homzr.lethal;heteroz. tumor susceptible |
| TP53 | p53 | 17p13 | Cell-cycle transcription factor (induces p21 exp.) | Li-Fraumeni | Yes | Yes | Disruptive (point mutation) | Varies | Yes | Yes | Homoz. tumor susceptible |
| CIP1 WAF1 CAP20 SD11 | p21 | 6p21 | Negative regulator of CDK–cyclin complexes | No | Yes | Yes | Disruptive (point mutation) | Yes | Yes | Yes | Homoz. normal but defective G1 arrest |
| KIP1 | p27 | 12p13 | Negative regulator of CDK–cyclin complexes | No | No |
| KIP2 | p57 | 11p15 | Negative regulator of CDK–cyclin complexes | ?Wilms (BWS) | Yes | ? |
| INK4A MTS1 CDKN2 MLM1 | p16 | 9p21 | Negative regulator ofCDK–cyclin complexes | Familial melanoma | Yes | Yes | Disruptive (deletion) | Yes |
| INK4B MTS2 CDKN2B | p15 | 9p21 | Negative regulator ofCDK–cyclin complexes | No | Yes | No |
| INK4C | p18 | 1p32 | Negative regulator of CDK–cyclin complexes | No | No |
| INK4D CDKN2D | p19 | 19p13 | Negative regulator of CDK–cyclin complexes | No | No |
| ARF1 | P16 (arf1) | 9p21 | Negative regulator of CDK–cyclin complexes | ?Familial melanoma | Yes | Yes | Disruptive |
| WT1 | WT1 | 11p13 | Transcription factor and RNA splicing regulator | Wilms’ (WAGR + DDS) | Yes | Yes | Varied (missenre mutations which abolish DNA binding capacity) | Yes | Yes | Yes | Homoz. lethal; heteroz. no phenotype |
| APC | APC | 5q21 | Regulation of cell adhesion and cell cycle | Familial adenomatous coli | Yes | Yes | Disruptive (truncating) | Yes | Yes | Yes | Homoz. lethal; heteroz. tumor susceptibility |
| NF1 | Neuro-fibromin | 17q12 | Regulator of G protein–mediated signaltransduction | Neurofibromatosis type 1 | No | Yes | Disruptive (truncating or loss of expression) | Yes | Yes | Homoz. lethal; heteroz. tumor susceptibility |
| NF 2 | Merlin | 22q12 | ?Regulator of membrane signaling; ?regulator of cell morphology | Neurofibromatosis type II | Yes | Yes | Disruptive (truncating) | Yes | Yes | Yes |
| VHL | VHL | 3p25 | Regulator of transcriptional elongation | VonHippel–Lindau | Yes | Yes | Disruptive (truncating and missense) | No | Yes |
| BRCA1 | BRCA1 | 17q21 | ? | Familialbreast/ovariancancer syndrome and familial site-specific breast cancer | Yes | Rare (ovarian cancan only) | Disruptive (truncating) | Yes | Yes | Yes | Homoz. lethal; heteroz. normal |
| BRCA2 | BRCA2 | 13q12 | ? | Familialbreast cancer | Yes | Rare (ovarian cancan only) | Disruptive (truncating mostly small deletions) |
| AT | ATM | 11q22 | Cell cycle regulation in response to DNA damage | Ataxia-telangiec-tasia | Yes | No | Disruptive (truncating and deletions) |
| MSH2 | MSH2 | 2p22 | DNA mismatch repair | HNPCC | ?No | Yes | Disruptive | Homoz. tumor susceptible |
| MLH1 | MLHl | 3p21–23 | " | HNPCC | Yes | Yes | — |
| PMS1 | PMS1 | 2q31–33 | " | HNPCC | ?No | Yes | — |
| PMS2 | PMS2 | 7p22 | " | HNPCC | ?No | Yes | Homoz. tumor susceptible + genetic instability |
| DCC | DCC | 18q21 | Regulation of cell growth and differentiation through cell–cell contact | No | Yes | Rare | Loss of expression, intron mutations, inissense mutations | Yes | Yes | Yes |
| DPC4 | DPC4 | 18q21 | TGFβ-mediated signal transduction | No | Yes | Yes | Disruptive |
| H19 | No protein | 11p15 | ?Regulation of expression of nearby... |
| Erscheint lt. Verlag | 13.9.1997 |
|---|---|
| Sprache | englisch |
| Themenwelt | Sachbuch/Ratgeber |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie | |
| Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik | |
| Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie | |
| Naturwissenschaften ► Biologie ► Humanbiologie | |
| Technik | |
| ISBN-10 | 0-08-056823-8 / 0080568238 |
| ISBN-13 | 978-0-08-056823-2 / 9780080568232 |
| Haben Sie eine Frage zum Produkt? |
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