Choosing between growth arrest and apoptosis through the retinoblastoma tumour suppressor protein, Abl and p73.
The choice between growth arrest and apoptosis is made during differentiation, leading to survival with permanent arrest (e.g. neurons), or to death (e.g. epithelium). Genotoxic stress can also cause growth arrest or apoptosis, in addition to the activation of cell cycle checkpoint pathways. The p53 tumour suppressor can simulate growth arrest and apoptosis in response to DNA damage. Thus, p53 alone is not sufficient to specify these two mutually exclusive fates in damaged cells. The retinoblastoma tumour suppressor protein (RB) is a necessary downstream effector in p53-mediated growth arrest. RB inhibits E2F and the nuclear c-Abl tyrosine kinase. Interestingly, E2F activates the transcription of p73 mRNA and c-Abl stabilizes the p73 protein and activates its pro-apoptotic function. Because of RB, the c-Abl/p73 apoptosis pathway is activated in S/G(2) cells but not in G(1) cells. Taken together, the current data suggests RB to be an important player in directing the choice between permanent arrest and apoptosis. The antagonism between RB and c-Abl/p73 may modulate the function of p53 to direct the choice between growth arrest and apoptosis in DNA damaged cells.
Wang
J Y
JY
Division of Biology and the Cancer Center, University of California, San Diego, La Jolla, CA 92093-0322, USA. jywang@ucsd.edu
Ki
S W
SW
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000502:physiology*; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000502:physiology*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D016315:Proto-Oncogene Proteins c-abl