Human Immunodeficiency Virus Type-1 Tat/Co-activator Acetyltransferase Interactions Inhibit p53Lys-320Acetylation and p53-responsive Transcription

Abstract

Patients with AIDS are at increased risk for developing various neoplasms, including Hodgkin's and nonHodgkin's lymphomas, Kaposi's sarcomas, and analrectal carcinomas, suggestive that human immunodeficiency virus type-1 infection might promote establishment of AIDS-related cancers. Tat, the viral transactivator, can be endocytosed by uninfected cells and has been shown to inhibit p53 functions, providing a candidate mechanism through which the human immunodeficiency virus type-1 might contribute to malignant transformation. Because Tat has been shown to interact with histone acetyltransferase domains of p300/cAMP-responsive element-binding protein (CREB)-binding protein and p300/CREB-binding protein-associated factor, we have investigated whether Tat might alter p53 acetylation and tumor suppressor-responsive transcription. Here, we demonstrate that both Tat and p53 co-localize with p300/ CREB-binding protein-associated factor and p300 in nuclei of IMR-32 human neuroblastoma cells and in PC-12 pheochromocytoma cells. Further, p53 trans-activation of the 14-3-3 promoter was markedly repressed by Tathistone acetyltransferase interactions, and p53 acetylation by p300/CREB-binding protein-associated factor on residue Lys 320 was diminished as a result of Tat-histone acetyltransferase binding in vivo and in vitro. Tat also inhibited p53 acetylation by p300 in a dosage-dependent manner in vitro. Finally, HIV-1-infected Molt-4 cells displayed reduced p53 acetylation on lysines 320 and 373 in response to UV irradiation. Our results allude to a mechanism whereby the human immunodeficiency virus type-1 trans-activator might impair tumor suppressor functions in immune/neuronal-derived cells, thus favoring the establishment of neoplasia during AIDS.

p73 Interacts with Human Immunodeficiency Virus Type 1 Tat in Astrocytic Cells and Prevents Its Acetylation on Lysine 28

“…Reciprocally, Tat inhibits the transcription of p53 through downregulation of the p53 promoter (28), while in our hands, Tat activates the p73 promoter (data not shown). Finally, Tat impairs p53 function by preventing its acetylation in immune/neuron-derived cells, thus favoring the establishment of neoplasia during AIDS (15). These results are in accord with our results obtained from protein-protein interaction where Tat affects p73 function by preventing its acetylation in U-87MG cells (data not shown).…”

Distinct GCN5/PCAF-containing complexes function as co-activators and are involved in transcription factor and global histone acetylation

“…Tat also prevents p53 transactivation on the 14-3-3-d promoter and at the same time, due to the Tat-PCAF interaction, cells bypass the G 2 /M checkpoint and do not go to apoptosis. In HIV infected cells the level of p53 does not increase after UV irradiation as the protein does not accumulate due to the lack of stabilizing acetylation (Harrod et al, 2003). All these phenomena together lead to an impaired tumour-suppressor function and result in the establishment of AIDS-related cancers.…”

Infection with E1B-mutant adenovirus stabilizes p53 but blocks p53 acetylation and activity through E1A

“…Herpes virus family members do not directly antagonize p53 either, but at least in the case of cytomegalovirus (human herpes virus type 5), the virus protein IE2 binds p300 and thus attenuates p53 activity (Hsu et al, 2004). The tat protein of human immunodeficiency virus also binds p300 and PCAF and it attenuates p53 activity (Harrod et al, 2003;Wong et al, 2005). Such indirect mechanisms may therefore suffice to avoid p53-induced cell death in many cases.…”