Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress.
The p53 tumor suppressor protein plays a key role in the regulation of stress-mediated growth arrest and apoptosis. Stress-induced phosphorylation of p53 tightly regulates its stability and transcriptional activities. Mass spectrometry analysis of p53 phosphorylated in 293T cells by active Jun NH2-terminal kinase (JNK) identified T81 as the JNK phosphorylation site. JNK phosphorylated p53 at T81 in response to DNA damage and stress-inducing agents, as determined by phospho-specific antibodies to T81. Unlike wild-type p53, in response to JNK stimuli p53 mutated on T81 (T81A) did not exhibit increased expression or concomitant activation of transcriptional activity, growth inhibition, and apoptosis. Forced expression of MKP5, a JNK phosphatase, in JNK kinase-expressing cells decreased T81 phosphorylation while reducing p53 transcriptional activity and p53-mediated apoptosis. Similarly transfection of antisense JNK 1 and -2 decreased T81 phosphorylation in response to UV irradiation. More than 180 human tumors have been reported to contain p53 with mutations within the region that encompasses T81 and the JNK binding site (amino acids 81 to 116). Our studies identify an additional mechanism for the regulation of p53 stability and functional activities in response to stress.
The Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
T
T
Buschmann
O
O
Potapova
A
A
Bar-Shira
V N
VN
Ivanov
S Y
SY
Fuchs
S
S
Henderson
V A
VA
Fried
T
T
Minamoto
D
D
Alarcon-Vargas
M R
MR
Pincus
W A
WA
Gaarde
N J
NJ
Holbrook
Y
Y
Shiloh
Z
Z
Ronai
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002455:Cell Division; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004355:Drug Stability; D054637:Dual-Specificity Phosphatases; D016158:Genes, p53; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D013058:Mass Spectrometry; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D054639:Mitogen-Activated Protein Kinase Phosphatases; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism; D013912:Threonine / Q000737:chemistry; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays
D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D016159:Tumor Suppressor Protein p53; D013912:Threonine; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C120407:DUSP10 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases; D017027:Protein Tyrosine Phosphatases