Transcriptional blockade induces p53-dependent apoptosis associated with translocation of p53 to mitochondria.
The tumor suppressor p53 functions as a transcriptional activator to induce cell cycle arrest and apoptosis in response to DNA damage. Although p53 was also shown to mediate apoptosis in a manner independent of its transactivation activity, the mechanism and conditions that trigger such cell death have remained largely unknown. We have now shown that inhibition of RNA polymerase II-mediated transcription by alpha-amanitin or RNA interference induced p53-dependent apoptosis. Inhibition of pol II-mediated transcription resulted in down-regulation of p21Cip1, which was caused by both transcriptional suppression and protein degradation, despite eliciting p53 accumulation, allowing the cells to progress into S phase and then to undergo apoptosis. This cell death did not require the transcription of p53 target genes and was preceded by translocation of the accumulated p53 to mitochondria. Our data thus suggested that blockade of pol II-mediated transcription induced p53 accumulation in mitochondria and was the critical factor for eliciting p53-dependent but transcription-independent apoptosis.
Arima
Yoshimi
Y
Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto 860-8556, Japan.
Nitta
Masayuki
M
Kuninaka
Shinji
S
Zhang
Dongwei
D
Fujiwara
Toshiyoshi
T
Taya
Yoichi
Y
Nakao
Mitsuyoshi
M
Saya
Hideyuki
H
D000256:Adenoviridae / Q000235:genetics; D000546:Amanitins / Q000737:chemistry / Q000378:metabolism; D017209:Apoptosis; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004249:DNA Damage; D015536:Down-Regulation; D016193:G1 Phase; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D021381:Protein Transport; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase; D013347:Subcellular Fractions; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays
D000546:Amanitins; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D012319:RNA Polymerase II