Nucleo-cytoplasmic communication in apoptotic response to genotoxic and inflammatory stress.
Genotoxic agents or inflammatory cytokines activate cellular stress responses and trigger programmed cell death. We have identified a signal transduction module, including three nuclear proteins that participate in the regulation of cell death induced by chemotherapeutic agents and tumor necrosis factor (TNF). In this nuclear signaling module, retinoblastoma protein (Rb) functions as an inhibitor of apoptotic signal transduction. Inactivation of Rb by phosphorylation or caspase-dependent cleavage/degradation is required for cell death to occur. Rb inhibits the Abl tyrosine kinase. Thus, Rb inactivation is a pre-requisite for Abl activation by DNA damage or TNF. Activation of nuclear Abl and its downstream effector p73 induces mitochondriadependent cell death. The involvement of these nuclear signal transducers in TNF induced apoptosis, which does not require new gene expression, indicates that nuclear events other than transcription can contribute to extrinsic apoptotic signal transduction.
Wang
Jean Yj
JY
Division of Biological Sciences and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0322, USA. jywang@ucsd.edu
D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D007249:Inflammation; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048069:Tumor Necrosis Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D016207:Cytokines; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins