Regulation of transactivation-independent proapoptotic activity of p53 by FOXO3a.
The tumor suppressor p53 can trigger cell death independently of its transcriptional activity through subcellular translocation and activation of proapoptotic Bcl-2 family members. The regulation of such activity of endogenous p53 in response to stress remains largely unknown. Here we show that nuclear, activated FOXO3a could impair p53 transcriptional activity. However, activation of FOXO3a either on serum starvation or by expressing a constitutively active form of FOXO3a could induce p53-dependent apoptosis, even in cells bearing a transcriptionally inactive form of p53. Furthermore, FOXO3a could promote p53 cytoplasmic accumulation by increasing its association with nuclear exporting machinery. Our data also suggest that PUMA and Bax are required for p53-dependent apoptosis in manner that is independent of p53 transcriptional activity.
You
Han
H
The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Suite 706, Toronto, ON, Canada M5G 2C1.
Yamamoto
Kazuo
K
Mak
Tak Wah
TW
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C494827:Bax protein, mouse; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein