Forms of Abl, such as Bcr-Abl, are exclusively cytoplasmic. If Bcr-Abl
Forms of Abl, such as Bcr-Abl, are exclusively cytoplasmic. If Bcr-Abl is trapped in the nucleus, it activates apoptosis. Essentially, an oncogene has thereby been converted into a tumor suppressor. .urthermore, this observation establishes the principle that the decision to undergo apoptosis can be regulated by the subcellular localization of c-Abl. The cellular responses to DNA damage are clearly of great interest as possible targets for anti-cancer strategies. Both Marion Boland (University College Dublin, Ireland) and William Beck (University of Illinois at Chicago, USA) focused on topoisomerase inhibitors. Boland described how inhibitors such as mitoxantrone result in the activation of the transcription factor N.B in a way that is dependent on topoisomerase and DNA damage. It is still not known, however, how components of the DNA-damage-response pathway interact with the N.B pathway. The use of genearray technology to identify differential gene regulation after treatment of cells with topoisomerase inhibitors was commented on by Beck: given the sheer number of genes that are either upregulated or downregulated, it is difficult to decide on the ones on which to focus. Beck also reported an enhanced interaction between topoisomerase II and Rb caused by some inhibitors, resulting in relocation of topoisomerase II to the nuclear periphery and activation of the c-Jun N-terminal kinase (JNK), followed by apoptosis. Intriguingly, Doug Green (La Jolla Institute for Allergy and Immunology, San Diego, USA) reported on a role for p53 as an anti-rheumatoid-arthritis factor, which suggests that it might perform a similar role in other hyper-proliferative diseases. Rheumatoid arthritis occurs PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28388412 when hyperplastic tissue invades and destroys joints. Reactive oxygen species, released at joints as a result of inflammatory damage, should normally result in p53-dependent apoptosis of synoviocytes (joint cells). Cells from the joints of rheumatoid arthritispatients have mutations in p53, however, suggesting a requirement for p53 in the efficient removal of hyperplastic tissue. Crucially, in a mouse model of rheumatoid arthritis, absence of p53 results in worse arthritis. Studies of DNA-damage signaling and apoptosis are clearly entering an exciting phase. .uture work will no doubt result in more detailed mechanistic understanding of the pathways involved as well increased understanding of what determines the central decision of whether to die or not to die. This is clearly cell-type-specific, and most probably changes during development. .inally, improved therapeutic strategies will eventually result from our increased understanding of the DNA-damage response.
BMC GenomicsResearchBioMed WP1066 supplier CentralOpen AccessMechanisms of chromosomal rearrangement in the human genomeAlbert G Tsai and Michael R Lieber*Address: USC Norris Comprehensive Cancer Ctr., Rm. 5428 Departments of Pathology, Biochemistry Molecular Biology, Molecular Microbiology Immunology, and of Biological Sciences (Section of Molecular Computational Biology), University of Southern California 1441 Eastlake Ave., MC9176 Los Angeles, CA 90089-9176, USA E-mail: Albert G Tsai – [email protected]; Michael R Lieber* – [email protected] *Corresponding authorfrom International Workshop on Computational Systems Biology Approaches to Analysis of Genome Complexity and Regulatory Gene Networks Singapore 20-25 November 2008 Published: 10 February 2010 BMC Genomics 2010, 11(suppl 1):S1 doi: 10.1186/1471-2164-11.
