HIV-1 viral protein r induces ERK and caspase-8-dependent apoptosis in renal tubular epithelial cells

Snyder, Alexandra; Alsauskas, Zygimantas; Leventhal, Jeremy S.; Rosenstiel, Philip; Gong, Peng; Chan, Justin; Barley, Kevin; He, John Cijiang; Klotman, Mary E.; Ross, Michael J.; Klotman, Paul E.

doi:10.1097/qad.0b013e328337b0ab

Cited by 51 publications

(41 citation statements)

References 43 publications

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“…Vpr---mediated apoptosis is complex and appears to invoke cell death via multiple pathways. Previous studies in have identified caspase activation and mitochondrial injury as a key component cell death in Vpr+ RTECs [138,139]. Thus, mitotic cell death is a novel mechanism of Vpr---induced apoptosis in RTECs in vitro, and my demonstration of high levels of mitotic marker PH3 in murine and human HIVAN kidney biopsies suggest mitotic progression may be relevant to HIV pathogenesis in vivo.…”

Section: Discussionmentioning

confidence: 86%

“…Vpr---mediated arrest in the G2 phase of the cell cycle is well established in both immortalized and primary renal tubule epithelial cells [60,138,139]. Previous work using pseudotyped lentiviral particles expressing single---gene constructs, pHR---Vpr, pHR---Tat, or pHR---Vif, confirm that the G2 arrest phenotype is Vpr---specific in RTEC model systems [60].…”

Section: Mechanisms Of Vpr-induced G 2 Arrest In the Kidneymentioning

confidence: 81%

“…We have previously shown that the HIV---1 accessory protein Vpr drives HIVAN---associated RTEC pathology, including G2/M arrest, apoptosis, and polyploidy [60,138,139]. Despite being reported in multiple in vitro systems [115,118], the temporal progression, molecular mechanism, and physiological significance of vpr---mediated polyploidy is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

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Polyploidy and Mitotic Cell Death Are Two Distinct HIV-1 Vpr-Driven Outcomes in Renal Tubule Epithelial Cells

Payne

Ramalingam

Fox

et al. 2018

J Virol

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Given the emerging epidemic of renal disease in HIV+ patients and the fact that HIV DNA and RNA persist in the kidneys of HIV+ individuals despite therapy, it is necessary to understand the role of direct HIV-1 infection of the kidney. HIV-associated kidney disease pathogenesis is attributed in large part to viral proteins. Expression of vpr in renal tubule epithelial cells (RTECs) induces G2 arrest, apoptosis and polyploidy.The ability of a subset of cells to overcome the G2 block and progress to polyploidy is not well understood. Polyploidy frequently associates with a bypass of cell death and disease pathogenesis. Given the ability of the kidney to serve as a unique compartment for HIV-1 infection, and the observed occurrence of polyploid cells in HIV+ renal cells, it is critical to understand the mechanisms and consequences of Vpr-induced polyploidy.Here I determined the effects of HIV-1 Vpr expression in renal cells using highly efficient transduction with VSV.G pseudotyped lentiviral vectors expressing vpr in the HK2 human tubule epithelial cell line. Using FACS, fluorescence microscopy, and live cell imaging I determined that G2 escape immediately precedes a critical junction between two distinct outcomes in Vpr+ RTECs: mitotic cell death and polyploidy. Vpr+ cells that evade aberrant mitosis and become polyploid have a substantially higher survival rate than those that undergo complete mitosis, and this survival correlates with enrichment for polyploidy in cell culture over time. Further, I identified a novel role for ATM kinase in promoting G2 arrest escape and polyploidy in Vpr+ RTECs. In summary, my work identifies ATM-dependent override of Vpr-mediated G2 arrest as a critical determinant of cell fate Vpr+ RTECs. Further, my work highlights how a poorly understood HIV mechanism, ploidy increase, may offer insight into key processes of reservoir establishment and disease pathogenesis in HIV+ kidneys.v researcher, but also her dedication to maintaining a fulfilling family life, and I aspire to achieve similar successes going forward. Dedication List of Tables List of FiguresI would like to thank my committee member and unofficial co---mentor, Dr.Donald Fox, for introducing me to the fascinating phenomenon of polyploidy. Dr. Fox's enthusiasm for science is unparalleled, and his mentorship and expertise were invaluable to the development and execution of my project. I also want to thank, Dr.David Howell, Dr. Micah Luftig and Dr. Robin Bachelder for serving on my committee.Their support, questions and feedback have made me a stronger scientist and contributed greatly to the completion of my dissertation.

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Section: Discussionmentioning

confidence: 86%

Section: Mechanisms Of Vpr-induced G 2 Arrest In the Kidneymentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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Polyploidy and Mitotic Cell Death Are Two Distinct HIV-1 Vpr-Driven Outcomes in Renal Tubule Epithelial Cells

Payne

Ramalingam

Fox

et al. 2018

J Virol

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“…Two major apoptotic pathways exploited by cells were discovered as an extrinsic or intrinsic pathway (31) by apical activation of caspase-8 or caspase-9, respectively. Early observations in various cell types showed that Vpr induced apoptosis either via the extrinsic pathway or intrinsic pathway (32)(33)(34)(35). Cell type-specific variations and context may account for these discrepancies (36).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 viral protein R (Vpr) induction of apoptosis and cell cycle arrest in multidrug-resistant colorectal cancer cells

Zhang

Wang

et al. 2012

Oncol Rep

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Abstract. Colorectal cancer is a significant health problem, and the advanced stages of the disease have a low response rate to chemotherapy and easily acquire chemoresistance. HIV-1 viral protein R (Vpr) has been shown to possess inhibitory effects on various malignant cells in vivo and in vitro. In this study, an Ad-Vpr construct was used to infect the multidrug-resistant human colorectal cancer HCT-8/5-FU(MDR) cell line in vitro for cell viability, apoptosis, gene expression and gene activity using the MTT, flow cytometry, immunoblotting and gel shift assays, respectively. The data showed that Ad-Vpr significantly reduced HCT-8/5-FU(MDR) cell viability in a dose-and time-dependent manner. Ad-Vpr infection promoted HCT-8/5-FU(MDR) cells to undergo apoptosis and to arrest at the G2 phase of the cell cycle. The G2 cell cycle protein Cyclin B1 accumulated in the cells after Ad-Vpr infection. Furthermore, Ad-Vpr induced activation of caspase-3 and -9, but not caspase-8, in HCT-8/5-FU(MDR) cells. Ad-Vpr suppressed expression of the Bcl-xl protein, but upregulated Bax expression and cytochrome c release from the mitochondria in HCT-8/5-FU(MDR) cells. Ad-Vpr infection also resulted in a time-dependent decrease in nuclear translocation of NF-κB/p65 protein and p65 DNA-binding activity in HCT-8/5-FU(MDR) cells. The data from the current study provide mechanistic insights into understanding the molecular basis and utility of Ad-Vpr as a novel anticancer agent for multidrug resistance in human colorectal cancer. IntroductionColorectal cancer is a significant health problem in the world, and is the third most common cancer in women and the fourth most common in men. More than half a million patients with colorectal cancer die of the disease annually worldwide (1,2). To date, surgical intervention is the most effective tool to cure colorectal cancer, whereas chemotherapy is another important means to treat colorectal cancer, especially for advanced staged disease. In those patients, chemotherapy appears to be the only therapeutic modality and offers some benefit. For chemotherapy, 5-fluorouracil (5-FU)-based regimens are the most common choice for patients. The combination of 5-FU with irinotecan and oxaliplatin has significantly improved the response rate of colorectal cancer patients. Additionally, combination regimens of 5-FU with irinotecan have been evaluated as the first-line therapeutic selection for advanced colorectal cancer with a response rate of 30-50% and an overall survival of 14-20 months (3,4). However, the response rate for these advanced targeted therapies and third-generation chemotherapies remains low (5). The reason may be due to innate and acquired chemoresistance (6) of colorectal cancer, which often leads to relapse and poor patient prognosis. Thus, a more aggressive and effective therapy to control colorectal cancer is imperative.To this end, our research focuses on the viral protein R (Vpr), which is an accessory protein and plays an important role in the regulation of nuclear import of the HIV-1 ...

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“…Its expression in tubular epithelial cells is associated with G2 cell cycle arrest, impaired cytokinesis and finally apoptosis (Zhong et al, 2005;Rosenstiel et al, 2008;2009b;Snyder et al, 2010;Vashistha et al, 2008). A synergistic effect of nef and vpr was observed in a study which showed that mice with both nef and vpr expression developed more severe nephropathy (Zuo et al, 2006).…”

Section: Amjmentioning

confidence: 99%

In-Depth Review of Human Immunodeficiency Virus-Associated Nephropathy

Permpalung

Chaiwatcharayut

Korpaisarn

et al. 2013

American Medical Journal

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HIV-1 viral protein r induces ERK and caspase-8-dependent apoptosis in renal tubular epithelial cells

Cited by 51 publications

References 43 publications

Polyploidy and Mitotic Cell Death Are Two Distinct HIV-1 Vpr-Driven Outcomes in Renal Tubule Epithelial Cells

Polyploidy and Mitotic Cell Death Are Two Distinct HIV-1 Vpr-Driven Outcomes in Renal Tubule Epithelial Cells

HIV-1 viral protein R (Vpr) induction of apoptosis and cell cycle arrest in multidrug-resistant colorectal cancer cells

In-Depth Review of Human Immunodeficiency Virus-Associated Nephropathy

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