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J Virol, August 1998, p. 6348-6355, Vol. 72, No. 8
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Phosphorylation of p53: a Novel Pathway for p53 Inactivation in Human T-Cell Lymphotropic Virus Type 1-Transformed Cells

Cynthia A. Pise-Masison,1 Michael Radonovich,1 Kazuyasu Sakaguchi,2 Ettore Appella,2 and John N. Brady1,*

Virus Tumor Biology Section, Laboratory of Receptor Biology and Gene Expression,1 and Laboratory of Cell Biology,2 National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055

Received 6 March 1998/Accepted 21 April 1998

Inhibition of p53 function, through either mutation or interaction with viral or cellular transforming proteins, correlates strongly with the oncogenic potential. Only a small percentage of human T-cell lymphotropic virus type 1 (HTLV-1)-transformed cells carry p53 mutations, and mutated p53 genes have been found in only one-fourth of adult T-cell leukemia cases. In previous studies, we demonstrated that wild-type p53 is stabilized and transcriptionally inactive in HTLV-1-transformed cells. Further, the viral transcriptional activator Tax plays a role in both the stabilization and inactivation of p53 through a mechanism involving the first 52 amino acids of p53. Here we show for the first time that phosphorylation of p53 inactivates p53 by blocking its interaction with basal transcription factors. Using two-dimensional peptide mapping, we demonstrate that peptides corresponding to amino acids 1 to 19 and 387 to 393 are hyperphosphorylated in HTLV-1-transformed cells. Moreover, using antibodies specific for phosphorylated Ser15 and Ser392, we demonstrate increased phosphorylation of these amino acids. Since HTLV-1 p53 binds DNA in a sequence-specific manner but fails to interact with TFIID, we tested whether phosphorylation of the N terminus of p53 affected p53-TFIID interaction. Using biotinylated peptides, we show that phosphorylation of Ser15 alone inhibits p53-TFIID interaction. In contrast, phosphorylation at Ser15 and -37 restores TFIID binding and blocks MDM2 binding. Our studies provide evidence that HTLV-1 utilizes the posttranslational modification of p53 in vivo to inactivate function of the tumor suppressor protein.

* Corresponding author. Mailing address: Virus Tumor Biology Section, Laboratory of Receptor Biology and Gene Expression, Building 41/B403, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5055. Phone: (301) 496-0986. Fax: (301) 496-4951. E-mail: bradyj{at}dce41.nci.nih.gov.

J Virol, August 1998, p. 6348-6355, Vol. 72, No. 8
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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