Suppression of p53-mediated growth factor withdrawal-induced apoptosis in the myeloid compartment by hematopoietic cytokines: an overview of hematopoiesis and apoptosis with a presentation of thrombopoietin and the M07E cell line as a model system.
The resistance of leukemic cells to apoptosis induction is one of the great obstacles in clinically alleviating the neoplastic state which they create. Even though p53 is the most commonly mutated protein found in tumors, there does exist the remaining body of cancers that possess wild-type p53. Within the hematopoietic compartment, the majority of acute myelogenous leukemia isolates fall into this latter category ([174, 175,375-377], for example). In particular, it is found that in most AML isolates p53 is genotypically wild-type but found to have an immunophenotype typical of mutant p53, or in the promoter conformation [170, 174,175,377]. The clinical significance of the research which aims to discern the molecular machinery involved in p53 conformational modulation must certainly include the notion that a therapeutic modality may be developed which interferes with the molecular process of shifting p53 from a viability-compromising suppressor conformation to the survival-enhancing promoter conformation. Further studies that investigate the interface between cytokine signaling transduction cascades and the subsystem(s) regulating the redox state of p53 are critical to advancing this field.
Ritchie
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A
Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, USA. aritchie@scripps.edu
Broxmeyer
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HE
D017209:Apoptosis / Q000187:drug effects*; D016207:Cytokines / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology*; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000737:chemistry* / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D013926:Thrombopoietin / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016207:Cytokines; D006133:Growth Substances; D016159:Tumor Suppressor Protein p53; D013926:Thrombopoietin