Involvement of miR-196a in HIV-associated neurocognitive disorders

Bagashev, Asen; Mukerjee, Ruma; Santerre, Maryline; Carpio-Cano, Fabiola E. Del; Shrestha, Jenny; Wang, Ying; He, Johnny J.; Sawaya, Bassel E.

doi:10.1007/s10495-014-1003-2

Cited by 15 publications

(16 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The rationale for using p73 came from our previous studies, where we showed that Tat protein could induce expression of p53 protein through induction of the p73 protein. We also demonstrated that p53 is a downstream target of p73 and that inhibition of p53 will not affect the endogenous level of p73 (10,38). As seen in Fig.…”

Section: Hiv-1 Tat Protein Alters Neuronal Functionssupporting

confidence: 69%

HIV-1 Tat protein promotes neuronal dysregulation by inhibiting E2F transcription factor 3 (E2F3)

Santerre

Bagashev

Gorecki

et al. 2019

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Edited by Paul E. FraserIndividuals who are infected with HIV-1 accumulate damage to cells and tissues (e.g. neurons) that are not directly infected by the virus. These include changes known as HIV-associated neurodegenerative disorder (HAND), leading to the loss of neuronal functions, including synaptic long-term potentiation (LTP). Several mechanisms have been proposed for HAND, including direct effects of viral proteins such as the Tat protein. Searching for the mechanisms involved, we found here that HIV-1 Tat inhibits E2F transcription factor 3 (E2F3), CAMP-responsive element-binding protein (CREB), and brain-derived neurotropic factor (BDNF) by up-regulating the microRNA miR-34a. These changes rendered murine neurons dysfunctional by promoting neurite retraction, and we also demonstrate that E2F3 is a specific target of miR-34a. Interestingly, bioinformatics analysis revealed the presence of an E2F3-binding site within the CREB promoter, which we validated with ChIP and transient transfection assays. Of note, luciferase reporter assays revealed that E2F3 up-regulates CREB expression and that Tat interferes with this up-regulation. Further, we show that miR-34a inhibition or E2F3 overexpression neutralizes Tat's effects and restores normal distribution of the synaptic protein synaptophysin, confirming that Tat alters these factors, leading to neurite retraction inhibition. Our results suggest that E2F3 is a key player in neuronal functions and may represent a good target for preventing the development of HAND.

show abstract

Section: Hiv-1 Tat Protein Alters Neuronal Functionssupporting

confidence: 69%

HIV-1 Tat protein promotes neuronal dysregulation by inhibiting E2F transcription factor 3 (E2F3)

Santerre

Bagashev

Gorecki

et al. 2019

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…The results showed that miR-196a has the potential to provide neuroprotective functions through regulation of the cytoskeleton in HD. Since several studies have addressed the effects of miR-196a on neuronal diseases [ 41 , 42 ], it is anticipated that the results of this analysis based on high throughput screening will provide insights that can aid in the development for therapeutic strategies for treating HD.…”

Section: Discussionmentioning

confidence: 99%

The Potential Regulatory Mechanisms of miR-196a in Huntington’s Disease through Bioinformatic Analyses

Lin

et al. 2015

PLoS ONE

View full text Add to dashboard Cite

High throughput screening is a powerful tool to identify the potential candidate molecules involved during disease progression. However, analysis of complicated data is one of the most challenging steps on the way to obtaining useful results from this approach. Previously, we showed that a specific miRNA, miR-196a, could ameliorate the pathological phenotypes of Huntington’s disease (HD) in different models, and performed high throughput screening by using the striatum of transgenic mice. In this study, we further tried to identify the potential regulatory mechanisms using different bioinformatic tools, including Database for Annotation, Visualization and Integrated Discovery (DAVID), Molecular Signatures Database (MSigDB), TargetScan and MetaCore. The results showed that miR-196a dominantly altered “ABC transporters”, “RIG-I-like receptor signaling pathway”, immune system”, “adaptive immune system”,“tissue remodeling and wound repair” and “cytoskeleton remodeling”. In addition, miR-196a also changed the expression of several well-defined pathways of HD, such as apoptosis and cell adhesion. Since these analyses showed the regulatory pathways are highly related to the modification of the cytoskeleton, we further confirmed that miR-196a could enhance the neurite outgrowth in neuroblastoma cells, suggesting miR-196a might provide beneficial functions through the alteration of cytoskeleton structures. Since impairment of the cytoskeleton has been reported in several neuronal diseases, this study will provide not only the potential working mechanisms of miR-196a but also insights for therapeutic strategies for use with different neuronal diseases.

show abstract

“…Most of these miRNAs are likely involved in key neural processes, such as axonal guidance and glucocorticoid signaling, thus confirming a role for Tat in HIV neuropathogenesis. In addition Tat deregulates neuronal functions by reducing the level of miR-196a, which causes an increase in the Abelson murine leukemia (c-Abl) protein, which phosphorylates the pro-apoptotic transcription factor p73, thus regulating its activity [77]. …”

Section: Regulation Of Mirna Expressionmentioning

confidence: 99%

Tat is a multifunctional viral protein that modulates cellular gene expression and functions

2017

View full text Add to dashboard Cite

The human immunodeficiency virus type I (HIV-1) has developed several strategies to condition the host environment to promote viral replication and spread. Viral proteins have evolved to perform multiple functions, aiding in the replication of the viral genome and modulating the cellular response to the infection. Tat is a small, versatile, viral protein that controls transcription of the HIV genome, regulates cellular gene expression and generates a permissive environment for viral replication by altering the immune response and facilitating viral spread to multiple tissues. Studies carried out utilizing biochemical, cellular, and genomic approaches show that the expression and activity of hundreds of genes and multiple molecular networks are modulated by Tat via multiple mechanisms.

show abstract

Involvement of miR-196a in HIV-associated neurocognitive disorders

Cited by 15 publications

References 61 publications

HIV-1 Tat protein promotes neuronal dysregulation by inhibiting E2F transcription factor 3 (E2F3)

HIV-1 Tat protein promotes neuronal dysregulation by inhibiting E2F transcription factor 3 (E2F3)

The Potential Regulatory Mechanisms of miR-196a in Huntington’s Disease through Bioinformatic Analyses

Tat is a multifunctional viral protein that modulates cellular gene expression and functions

Contact Info

Product

Resources

About