Dysregulation of the Tumor Suppressor Tip60 and ATM Signaling Paradigm by the HIV Transactivator of Transcription

Abstract

Despite the longevity afforded by modern anti‐retroviral therapy, long‐term HIV infection increases the risk for pulmonary co‐morbidities associated with cell cycle dysregulation including lung cancer and pulmonary arterial hypertension. As such, we postulate that select viral factors, in particular the HIV transactivator of transcription (Tat), interfere with cellular processes involving tumor suppressors and other cell cycle regulators during chronic infection. Tat is well known to inhibit the activity of the tumor suppressor Tat Interacting Protein 60 kDa (Tip60), an acetyltransferase critical in the progression to cell cycle arrest and/or apoptosis. In response to stressors such as DNA damage and oxidative stress, Tip60 activates the cell cycle master regulator kinase Ataxia Telangiectasia Mutated (ATM) via acetylation, initiating a signaling cascade that culminates in the activation of a DNA damage response resulting in both short and long term cellular arrest. Thus, we hypothesize that inhibition of Tip60 by Tat interferes with cellular arrest in responses to these stressors and results in abnormal proliferation. We addressed the hypothesis using HeLa cells stably transfected to express Tat (HeLa‐TatIII). Utilizing an ATP based luminescent cell viability assay, we observed accelerated cell proliferation in HeLa‐TatIII compared to its HeLa wild‐type counterpart. Furthermore, immunoprecipitation experiments in HeLa‐WT cells confirmed a physical interaction between Tat and Tip60. Acetylation by Tip60 results in autophosphorylation of ATM at ser1981, and this phosphorylation event is a canonical marker for ATM activation. As such, we determined the phosphorylation state of ATM ser1981 after treatment with doxorubicin in HeLa‐WT and HeLa‐TatIII cells. We found that, following treatment with doxorubicin, ATM phosphorylation at ser1981 was severely attenuated in HeLa‐TatIII cells compared to HeLa‐WTs, suggesting a role for Tat in the inhibition of ATM activation. Taken together, these data support the role of the HIV Tat protein in dysregulation of cell cycle arrest via ATM signaling pathways. Whether HIV promotes cellular proliferation in co‐morbidities such as lung cancer and pulmonary arterial hypertension via these pathways remains to be addressed.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.