Human T-cell leukemia virus type-1-encoded protein HBZ represses p53 function by inhibiting the acetyltransferase activity of p300/CBP and HBO1.
Adult T-cell leukemia (ATL) is an often fatal malignancy caused by infection with the complex retrovirus, human T-cell Leukemia Virus, type 1 (HTLV-1). In ATL patient samples, the tumor suppressor, p53, is infrequently mutated; however, it has been shown to be inactivated by the viral protein, Tax. Here, we show ... that another HTLV-1 protein, HBZ, represses p53 activity. In HCT116 p53+/+ cells treated with the DNA-damaging agent, etoposide, HBZ reduced p53-mediated activation of p21/CDKN1A and GADD45A expression, which was associated with a delay in G2 phase-arrest. These effects were attributed to direct inhibition of the histone acetyltransferase (HAT) activity of p300/CBP by HBZ, causing a reduction in p53 acetylation, which has be linked to decreased p53 activity. In addition, HBZ bound to, and inhibited the HAT activity of HBO1. Although HBO1 did not acetylate p53, it acted as a coactivator for p53 at the p21/CDKN1A promoter. Therefore, through interactions with two separate HAT proteins, HBZ impairs the ability of p53 to activate transcription. This mechanism may explain how p53 activity is restricted in ATL cells that do not express Tax due to modifications of the HTLV-1 provirus, which accounts for a majority of patient samples.
Mesh Terms:
Acetylation, Animals, Basic-Leucine Zipper Transcription Factors, Blotting, Western, Cell Cycle Proteins, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Etoposide, G2 Phase Cell Cycle Checkpoints, Gene Expression Regulation, Neoplastic, HCT116 Cells, HEK293 Cells, HeLa Cells, Histone Acetyltransferases, Human T-lymphotropic virus 1, Humans, Nuclear Proteins, Protein Binding, Retroviridae Proteins, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Protein p53, p300-CBP Transcription Factors
Acetylation, Animals, Basic-Leucine Zipper Transcription Factors, Blotting, Western, Cell Cycle Proteins, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Etoposide, G2 Phase Cell Cycle Checkpoints, Gene Expression Regulation, Neoplastic, HCT116 Cells, HEK293 Cells, HeLa Cells, Histone Acetyltransferases, Human T-lymphotropic virus 1, Humans, Nuclear Proteins, Protein Binding, Retroviridae Proteins, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Protein p53, p300-CBP Transcription Factors
Oncotarget
Date: Jan. 12, 2016
PubMed ID: 26625199
View in: Pubmed Google Scholar
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