An RGD Containing peptide from HIV-1 TAT-(65–80) modulates protooncogene expression in human bronchoalveolar carcinoma cell line, A549

Abstract

Tat (transactivator of transcription) is essential for HIV-1 replication in vivo and in vitro. Tat-(65-80), an RGD containing domain, has been shown to regulate proliferative function of a variety of cell lines, including a human adenocarcinoma cell line, A549. The exact cellular and molecular mechanisms by which these effects are mediated, remain unknown. To evaluate the hypothesis that Tat-(65-80) modulates the expression of immediate early genes (IEG) c-jun, c-myc, c-fos and the tumor suppressor gene p53, serum starved A549 cells were incubated with Tat-(65-80) or heat-inactivated Tat-(65-80) at 10 ng/ml. Total cellular RNA was isolated from the cells at various time points (0-24 hours). In each case, 5 micrograms of RNA was reverse transcribed in 20 microliters of reaction volume. Equal amounts of cDNA were subjected to polymerase chain reaction (PCR) and analyzed by electrophoresis. The photographic negatives of the ethidium bromide stained gels were quantitated by densitometric scanning and normalized to corresponding beta-actin PCR products. Treatment with Tat-(65-80) showed a twofold induction of c-jun at 0.5 h. Peak expression occurred at 60 minutes and remained above baseline at 24 hours (h). c-myc was increased at 0.5 h, reached a twofold increase at 2 h and remained above baseline at 24 h. c-fos increased seven fold at 0.5 h and declined subsequently to baseline at 8 h. p-53 gene was reduced fivefold at 0.5 h and remained downregulated thereafter. These results show that Tat-(65-80) can modulate growth related genes in human lung epithelial cells.

Malignancy‐related causes of death in human immunodeficiency virus–infected patients in the era of highly active antiretroviral therapy

“…30 -33 Some in vitro studies have shown that the HIV tat gene may modulate the expression of certain protooncogenes (c-myc, c-fos, and p53) in malignant cells. 34 The role of HIV itself in the development of solid malignancies, if it exists, probably is relatively minor compared with the impact of risk factors such as tobacco use, alcohol use, poor nutrition, coinfection with other protooncongene viruses (e.g., hepatitis, human papillomavirus, etc. ), and immunodepression, which often is present in HIV-infected patients and should be the target of preventive and curative strategies.…”

HIV Infection in the Etiology of Lung Cancer: Confounding, Causality, and Consequences

“…HIV itself might have a direct oncogenic role. Although limited experimental data suggest that the HIV tat gene product may modulate expression of growth-related genes, amplification of HIV sequences in lung carcinoma tissue has not been demonstrated (55,56). Further, the limited data on risk for lung cancer associated with HIV RNA levels has not been suggestive of a strong association (4,36,41).…”

Loss of G 1 /S Checkpoint in Human Immunodeficiency Virus Type 1-Infected Cells Is Associated with a Lack of Cyclin-Dependent Kinase Inhibitor p21/Waf1

“…Tat-(65-80), an RGD-containing domain, has been shown to regulate the proliferative functions of a variety of cell lines, including a human adenocarcinoma cell line, A549. Treatment with Tat-(65-80) has been shown to reduce the p53 gene product fivefold, whereas c-fos gene transcription increased sevenfold at 0.5 h posttreatment and subsequently declined to baseline levels at 8 h. Therefore, it was suggested that Tat-(65-80) can modulate growth-related genes in cells (12). A similar result has also been reported in which Tat inhibits the transcription of p53, and the downregulation of p53 by Tat may be involved in the development of AIDS-related malignancies (26).…”