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Molecular and Cellular Biology, April 2001, p. 2743-2754, Vol. 21, No. 8
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.8.2743-2754.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Jun NH2-Terminal Kinase Phosphorylation of p53 on Thr-81 Is Important for p53 Stabilization and Transcriptional Activities in Response to Stress

Thomas Buschmann,1 Olga Potapova,2 Anat Bar-Shira,3 Vladimir N. Ivanov,1 Serge Y. Fuchs,1,dagger Scott Henderson,4 Victor A. Fried,5 Toshinari Minamoto,6 Dania Alarcon-Vargas,1 Matthew R. Pincus,7 William A. Gaarde,8 Nikki J. Holbrook,2 Yosef Shiloh,3 and Ze'ev Ronai1,*

The Ruttenberg Cancer Center1 and Department of Cell Biology,4 Mount Sinai School of Medicine, New York, Department of Cell Biology and Anatomy, New York Medical College, Valhalla,5 and Department of Pathology and Laboratory Medicine, State University of New York Health Science Center, Brooklyn,7 New York; Cell Stress and Aging Section, Laboratory of Biological Chemistry, National Institute on Aging, National Institutes of Health, Baltimore, Maryland2; Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel3; Cancer Research Institute, Kanazawa University, Kanazawa, Japan6; and Isis Pharmaceuticals Inc., Carlsbad, California8

Received 9 October 2000/Returned for modification 28 November 2000/Accepted 24 January 2001

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.

* Corresponding author. Mailing address: The Ruttenberg Cancer Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1130, New York, NY 10029-6574. Fax: (212) 849-2446. E-mail: zeev.ronai{at}mssm.edu.

dagger Present address: Department of Animal Biology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA 19104-6046.

Molecular and Cellular Biology, April 2001, p. 2743-2754, Vol. 21, No. 8
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.8.2743-2754.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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