title: Human immunodeficiency virus type-1 Tat/co-activator acetyltransferase interactions inhibit p53Lys-320 acetylation and p53-responsive transcription.
abstract: Patients with AIDS are at increased risk for developing various neoplasms, including Hodgkin's and non-Hodgkin's lymphomas, Kaposi's sarcomas, and anal-rectal carcinomas, suggestive that human immunodeficiency virus type-1 infection might promote establishment of AIDS-related cancers. Tat, the viral trans-activator, 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 14-3-3varsigma promoter was markedly repressed by Tat-histone 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.
authors.affiliation: Laboratory of Molecular Virology, Department of Biological Sciences, Southern Methodist University, Dallas, Texas 75275-0376, USA. rharrod@mail.smu.edu
authors.forename: Robert
authors.initials: R
authors.lastname: Harrod
authors.forename: Janos
authors.initials: J
authors.lastname: Nacsa
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hansen
authors.forename: Tatiana
authors.initials: T
authors.lastname: Karpova
authors.forename: James
authors.initials: J
authors.lastname: McNally
authors.forename: Genoveffa
authors.initials: G
authors.lastname: Franchini
mesh_terms: D000107:Acetylation / Q000528:radiation effects; D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism*; D006678:HIV / Q000378:metabolism*; D015497:HIV-1; D051548:Histone Acetyltransferases; D006801:Humans; D009447:Neuroblastoma; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D014466:Ultraviolet Rays; D050880:p300-CBP Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D000099224:p300-CBP-Associated Factor
chemical_list: D000123:Acetyltransferases; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004317:Doxorubicin; D015696:Gene Products, tat; D051548:Histone Acetyltransferases; D010446:Peptide Fragments; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D000099224:p300-CBP-Associated Factor