Book contents
- Frontmatter
- Dedication
- Contents
- List of Contributors
- Preface
- Part 1.1 Analytical techniques: analysis of DNA
- Part 1.2 Analytical techniques: analysis of RNA
- Part 2.1 Molecular pathways underlying carcinogenesis: signal transduction
- Part 2.2 Molecular pathways underlying carcinogenesis: apoptosis
- Part 2.3 Molecular pathways underlying carcinogenesis: nuclear receptors
- Part 2.4 Molecular pathways underlying carcinogenesis: DNA repair
- Part 2.5 Molecular pathways underlying carcinogenesis: cell cycle
- 38 Cell cycle: mechanisms of control and dysregulation in cancer
- 39 DNA-damage-induced apoptosis
- Part 2.6 Molecular pathways underlying carcinogenesis: other pathways
- Part 3.1 Molecular pathology: carcinomas
- Part 3.2 Molecular pathology: cancers of the nervous system
- Part 3.3 Molecular pathology: cancers of the skin
- Part 3.4 Molecular pathology: endocrine cancers
- Part 3.5 Molecular pathology: adult sarcomas
- Part 3.6 Molecular pathology: lymphoma and leukemia
- Part 3.7 Molecular pathology: pediatric solid tumors
- Part 4 Pharmacologic targeting of oncogenic pathways
- Index
- References
39 - DNA-damage-induced apoptosis
from Part 2.5 - Molecular pathways underlying carcinogenesis: cell cycle
Published online by Cambridge University Press: 05 February 2015
- Frontmatter
- Dedication
- Contents
- List of Contributors
- Preface
- Part 1.1 Analytical techniques: analysis of DNA
- Part 1.2 Analytical techniques: analysis of RNA
- Part 2.1 Molecular pathways underlying carcinogenesis: signal transduction
- Part 2.2 Molecular pathways underlying carcinogenesis: apoptosis
- Part 2.3 Molecular pathways underlying carcinogenesis: nuclear receptors
- Part 2.4 Molecular pathways underlying carcinogenesis: DNA repair
- Part 2.5 Molecular pathways underlying carcinogenesis: cell cycle
- 38 Cell cycle: mechanisms of control and dysregulation in cancer
- 39 DNA-damage-induced apoptosis
- Part 2.6 Molecular pathways underlying carcinogenesis: other pathways
- Part 3.1 Molecular pathology: carcinomas
- Part 3.2 Molecular pathology: cancers of the nervous system
- Part 3.3 Molecular pathology: cancers of the skin
- Part 3.4 Molecular pathology: endocrine cancers
- Part 3.5 Molecular pathology: adult sarcomas
- Part 3.6 Molecular pathology: lymphoma and leukemia
- Part 3.7 Molecular pathology: pediatric solid tumors
- Part 4 Pharmacologic targeting of oncogenic pathways
- Index
- References
Summary
Overview
Regulation of DNA-damage-induced apoptosis is important to oncology in two ways. First, the majority of carcinogens are genotoxins that cause DNA damage and the apoptotic response to carcinogens is an important tumor-suppression mechanism. Second, a number of mainstay cancer therapeutic agents are genotoxins and their efficacies can be influenced by the robustness of DNA-damage-induced apoptosis in tumor cells. This chapter focuses on a network of nuclear factors involved in the transmission of DNA-damage signals to the intrinsic apoptotic machinery. These nuclear factors include DNA-damage sensors, the PIKK-family of protein kinases that these sensors activate, and three downstream nuclear effectors, p53, Abl, and caspase-2 (Figure 39.1). We have chosen to focus on this collection of nuclear factors, which represent only a subset of the DNA-damage signaling pathways, to illustrate two major points: (i) DNA-damage-induced apoptosis is regulated by nuclear proteins that also regulate DNA repair and (ii) DNA damage signals can be independently transmitted by several downstream effectors, i.e. p53, Abl, and caspase-2, to activate intrinsic apoptosis.
DNA damage does not always activate apoptosis
The concept of a linear, hard-wired signaling pathway that links lesions in genomic DNA to the apoptosis machinery would predict that DNA damage should always lead to cell killing, but this is not the case. In cells that undergo DNA-damage-induced apoptosis, death is invariably a delayed response requiring hours of deliberation. Generally speaking, delayed responses to biological perturbations are those that involve the reprogramming of gene expression, which, by nature of the transcription and translation processes, requires time. As the reprogramming of gene expression is under the hierarchical control of a multitude of genetic and epigenetic factors, activation of DNA-damage-induced apoptotic response is highly dependent on the lineage and the developmental stage of a cell. In addition to apoptosis, DNA-damaged cells can choose to undergo premature senescence or adaptation, where cells resume proliferation despite the persistence of DNA lesions. The choice a cell makes among these delayed responses to DNA damage is determined by how a cell reprograms its gene expression.
- Type
- Chapter
- Information
- Molecular OncologyCauses of Cancer and Targets for Treatment, pp. 465 - 472Publisher: Cambridge University PressPrint publication year: 2013