Cancer stem cells have originally been identified in leukemia and later in several solid tumor types. They have very different properties from the bulk of the tumor as they divide much more slowly and have very efficient drug resistance mechanisms. Current treatments might largely spare cancer stem cells. This book looks at recent developments in the field of cancer stem cells and the possible impact for the identification of novel treatment paradigms for cancer.

The ubiquitin system has two major functions in eukaryotic cells: it r- ulates protein degradation, which is essential for normal cellular fu- tion and for the removal of potentially harmful, damaged, or misfolded proteins, and it controls protein activity by regulating protein-protein interactions and subcellullar localization. The ubiquitin system is thus involved in processes as diverse as cell cycle progression, signal tra- duction, gene transcription, and DNA repair. Not surprisingly, defects in the ubiquitin system have been linked with numerous diseases such as cancer, in?ammation, central nervous system disorders, and metabolic dysfunction. Ubiquitin is a highly conserved 76-amino acid protein which is transferred to its target protein in an ATP-dependent manner. This post-translational modi?cation takes place in a hierarchical, three-step fashion involving an E1 ubiquitin-activating enzyme, an E2 ubiquit- conjugating enzyme, and an E3 ubiquitin ligase. Substrate speci?city is predominantly controlled by members of a large family of E3 - zymes, which form complexes with the proteins that will be modi?ed. This ultimately leads to the covalent attachment of the C-terminus of ubiquitin to usually an?-amino group of a lysine residue in the targeted protein. Additional ubiquitin transfer to lysine-48 of ubiquitin itself will form a polyubiquitin chain, which usually targets the conjugate for degradation by the proteasome. By contrast, mono- or polyubiquityla- VI Preface tion involving lysine-63 is normally involved in the control of protein activity. Ubiquitylation can be reverted by deubiquitylating enzymes, of which approximately 95 exist in mammals.

Cancer stem cells werehave originally been identified in leukemia and later in several solid tumor types. They have very different properties from the bulk of the tumor, as they divide much more slowly and have very efficient drug- resistance mechanisms. Current treatments might largely spare cancer stem cells, thus leading to tumor recurrence and metastasis. The recent identification of growth and differentiation pathways responsible for cancer stem cell proliferation and survival will help in the discovery identification of novel therapeutic targets. Developing selective drugs against cancer stem cells offers great therapeutic opportunities but also provides for major challenges regarding preclinical models, therapeutic windows, and clinical study end points.

Methylation of DNA at cytosine residues as well as post-translational modifications of histones, including phosphorylation, acetylation, methylation and ubiquitylation, contribute to the epigenetic information carried by chromatin. These changes play an important role in the regulation of gene expression by modulating the access of regulatory factors to the DNA. The use of a combination of biochemical, genetic and structural approaches has allowed demonstration of the role of chromatin structure in transcriptional control. The structure of nucleosomes has been elucidated and enzymes involved in DNA or histone modifications have been extensively characterized. Since deregulation of epigenetic marks has been reported in many cancers, a better understanding of the underlying molecular mechanisms bears the promise that new drug targets may soon be found. The newest developments in this quickly developing field are presented in this book.

Methylation of DNA at cytosine residues as well as post-translational modifications of histones, including phosphorylation, acetylation, methylation and ubiquitylation, contribute to the epigenetic information carried by chromatin. These changes play an important role in the regulation of gene expression by modulating the access of regulatory factors to the DNA. The use of a combination of biochemical, genetic and structural approaches has allowed demonstration of the role of chromatin structure in transcriptional control. The structure of nucleosomes has been elucidated and enzymes involved in DNA or histone modifications have been extensively characterized. Since deregulation of epigenetic marks has been reported in many cancers, a better understanding of the underlying molecular mechanisms bears the promise that new drug targets may soon be found. The newest developments in this quickly developing field are presented in this book.

The ubiquitin system has two major functions in eukaryotic cells: it r- ulates protein degradation, which is essential for normal cellular fu- tion and for the removal of potentially harmful, damaged, or misfolded proteins, and it controls protein activity by regulating protein-protein interactions and subcellullar localization. The ubiquitin system is thus involved in processes as diverse as cell cycle progression, signal tra- duction, gene transcription, and DNA repair. Not surprisingly, defects in the ubiquitin system have been linked with numerous diseases such as cancer, in?ammation, central nervous system disorders, and metabolic dysfunction. Ubiquitin is a highly conserved 76-amino acid protein which is transferred to its target protein in an ATP-dependent manner. This post-translational modi?cation takes place in a hierarchical, three-step fashion involving an E1 ubiquitin-activating enzyme, an E2 ubiquit- conjugating enzyme, and an E3 ubiquitin ligase. Substrate speci?city is predominantly controlled by members of a large family of E3 - zymes, which form complexes with the proteins that will be modi?ed. This ultimately leads to the covalent attachment of the C-terminus of ubiquitin to usually an?-amino group of a lysine residue in the targeted protein. Additional ubiquitin transfer to lysine-48 of ubiquitin itself will form a polyubiquitin chain, which usually targets the conjugate for degradation by the proteasome. By contrast, mono- or polyubiquityla- VI Preface tion involving lysine-63 is normally involved in the control of protein activity. Ubiquitylation can be reverted by deubiquitylating enzymes, of which approximately 95 exist in mammals.