Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity.
Cellular damage invoked by reactive oxygen species plays a key role in the pathobiology of cancer and aging. Forkhead box class O (FoxO) transcription factors are involved in various cellular processes including cell cycle regulation, apoptosis and resistance to reactive oxygen species, and studies in animal models have shown that these transcription factors are of vital importance in tumor suppression, stem cell maintenance and lifespan extension. Here we report that the activity of FoxO in human cells is directly regulated by the cellular redox state through a unique mechanism in signal transduction. We show that reactive oxygen species induce the formation of cysteine-thiol disulfide-dependent complexes of FoxO and the p300/CBP acetyltransferase, and that modulation of FoxO biological activity by p300/CBP-mediated acetylation is fully dependent on the formation of this redox-dependent complex. These findings directly link cellular redox status to the activity of the longevity protein FoxO.
Dansen
Tobias B
TB
Department of Physiological Chemistry, University Medical Center Utrecht, Utrecht, The Netherlands. t.b.dansen@umcutrecht.nl
Smits
Lydia M M
LM
van Triest
Miranda H
MH
de Keizer
Peter L J
PL
van Leenen
Dik
D
Koerkamp
Marian Groot
MG
Szypowska
Anna
A
Meppelink
Amanda
A
Brenkman
Arjan B
AB
Yodoi
Junji
J
Holstege
Frank C P
FC
Burgering
Boudewijn M T
BM
D000107:Acetylation; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D002470:Cell Survival; D003545:Cysteine / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010084:Oxidation-Reduction; D010545:Peroxides / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013879:Thioredoxins / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D010545:Peroxides; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D013879:Thioredoxins; D050880:p300-CBP Transcription Factors; D008239:Lysine; D003545:Cysteine