Activation of Egr-1 Expression in Astrocytes by HIV-1 Tat: New Insights into Astrocyte-Mediated Tat Neurotoxicity

Fan, Yan; Zou, Wei; Green, Linden A.; Kim, Byung Oh; He, Johnny J.

doi:10.1007/s11481-010-9217-8

Cited by 39 publications

(41 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings suggested that cocaine-mediated activation of ERK and JNK MAPKs pathways were upstream of Egr-1. Interestingly, our findings are in agreement with a report from Fan et a l demonstrating that HIV Tat-mediated astrogliosis involves activation of Egr-1 and transcriptional upregulation of GFAP [7]. It is likey that Egr-1 is one of the common signaling molecules critical for both Tat and cocaine-mediated activation of astrocytes.…”

Section: Discussionsupporting

confidence: 93%

“…Since acute cocaine administration has been shown to elicit rapid and transient induction of several immediate-early genes in the brain, including Egr-1, c-fos and junB [30] and Egr-1 has been suggested to function as a molecular switch that coordinates changes in GFAP expression [31], we sought to examine whether cocaine-mediated induction of GFAP expression involved activation of Egr-1 in astrocytes. As shown in Figure 4a & b, cocaine up-regulated expression of Egr-1 in a time-dependent manner with peak expression elicited between 1–3h and a decline thereafter, both in A172 cells and in mouse primary astrocytes.…”

Section: Resultsmentioning

confidence: 99%

“…Cocaine, often abused by HIV-infected patients, has been suggested to hasten as well as worsen disease pathogenesis [6]. While the effects of HIV viral proteins have been well studied [7, 8], how drugs of abuse such as cocaine can cause glial activation and concomitant neuronal toxicity remains less clear. In the current study we sought to examine the molecular mechanisms of cocaine-mediated induction of GFAP expression in astrocyte cultures and in mice injected with cocaine.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Role of Sigma Receptor in Cocaine-Mediated Induction of Glial Fibrillary Acidic Protein: Implications for HAND

et al. 2015

View full text Add to dashboard Cite

Cocaine abuse has been shown to accelerate the progression of human immunodeficiency virus (HIV)-1-associated neurological disorders (HANDs) partially through increasing neuroinflammatory response mediated by activated astrocytes; however, the detailed molecular mechanism of cocaine mediated astrocytes activation is unclear. In the current study, we demonstrated increased astrogliosis in the cortical regions of brains from HIV+ cocaine abusers compared with the HIV+ group without cocaine abuse. We next sought to explore whether cocaine exposure could result in increased expression of Glial Fibrillary Acidic Protein (GFAP), a filament protein critical for astrocyte activation. Exposure of cocaine to astrocytes resulted in rapid translocation of sigma receptor to the plasma membrane with subsequent activation of downstream signaling pathways. Using a pharmacological approach, we provide evidence that cocaine-mediated upregulation of GFAP expression involved activation of mitogen-activated protein kinases (MAPKs) signaling with subsequent downstream activation of the early growth response gene 1 (Egr-1). Egr-1 activation in turn, caused transcriptional regulation of GFAP. Corroboration of these findings in vivo demonstrated increased expression of GFAP in the cortical region of mice treated with cocaine compared with the saline injected controls. A thorough understanding of how cocaine mediates astrogliosis could have implications for the development of therapeutic interventions aimed at HIV-infected cocaine abusers.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Role of Sigma Receptor in Cocaine-Mediated Induction of Glial Fibrillary Acidic Protein: Implications for HAND

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Studies, including ours, have shown that astrocytes potentiate Tat neurotoxicity (16,20,22), probably through Tat-mediated transcriptional activation of glial fibrillary acidic protein (GFAP) expression (29 -31). Of particular note is that Tat expression in astrocytes alone is sufficient to induce pathological changes such as reactive astrocytes or astrocytosis, loss of neuron axons and dendrites, and neurobehavioral deficits such as impaired motor and cognitive functions in the CNS reminiscent of HIVassociated MCMD (22,29,32,33). These findings support the notion that astrocyte-mediated Tat neurotoxicity plays important roles in HIV/neuroAIDS.…”

supporting

confidence: 55%

HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity

Fan

2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Tat interaction with astrocytes has been shown to be important for Tat neurotoxicity and HIV/neuroAIDS. We have recently shown that Tat expression leads to increased glial fibrillary acidic protein (GFAP) expression and aggregation and activation of unfolded protein response/endoplasmic reticulum (ER) stress in astrocytes and causes neurotoxicity. However, the exact molecular mechanism of astrocyte-mediated Tat neurotoxicity is not defined. In this study, we showed that neurotoxic factors other than Tat protein itself were present in the supernatant of Tat-expressing astrocytes. Two-dimensional gel electrophoresis and mass spectrometry revealed significantly elevated lysosomal hydrolytic enzymes and plasma membraneassociated proteins in the supernatant of Tat-expressing astrocytes. We confirmed that Tat expression and infection of pseudotyped HIV.GFP led to increased lysosomal exocytosis from mouse astrocytes and human astrocytes. We found that Tatinduced lysosomal exocytosis was tightly coupled to astrocytemediated Tat neurotoxicity. In addition, we demonstrated that Tat-induced lysosomal exocytosis was astrocyte-specific and required GFAP expression and was mediated by ER stress. Taken together, these results show for the first time that Tat promotes lysosomal exocytosis in astrocytes and causes neurotoxicity through GFAP activation and ER stress induction in astrocytes and suggest a common cascade through which aberrant astrocytosis/GFAP up-regulation potentiates neurotoxicity and contributes to neurodegenerative diseases.

show abstract

“…ERCC1 plays a pivotal role in several DNA repair pathways and also forms a structure-specific heterodimeric endonuclease with xeroderma pigmentosum complementation group F, which cleaves damaged 5'-DNA in the lesion (Doll et al, 2010). Previous research has shown a strong association between the decrease in ERCC1 expression and the occurrence of cancer (Fan et al, 2011). The results of our study indicated that low ERCC1 expression was correlated with poor prognosis of EC, and SNX-2112 could be used to treat EC by increasing the expression of ERCC1.…”

Section: Discussionmentioning

confidence: 99%

Effect of SNX-2112 on proliferation of esophageal cancer cells via regulation of excision repair cross-complementing 1, epidermal growth factor receptor, and p53 expression

Cy¹,

Ren²,

Yd³

2016

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. SNX-2112 is a potential molecular targeted therapeutic drug against esophageal cancer (EC). However, its exact mechanism of action remains to be explained. The aim of this study was to investigate the effect of SNX-2112 on excision repair cross-complementing 1 (ERCC1), epidermal growth factor receptor (EGFR), and p53, to elucidate the mechanism of action of SNX-2112 on EC. Fresh tumor sections were surgically obtained from 65 patients with EC, and the expression of ERCC1, EGFR, and p53 was determined by immunohistochemical staining. Furthermore, the effect of SNX-2112 (0.2 µM) on the proliferation of EC-9706 cells and the expression of ERCC1, EGFR, and p53 in these cells were analyzed by a cell proliferation assay and western blot, respectively. We observed a significant decrease and increase in ERCC1 (P = 0.001) and p53 (P = 0.043) expression, respectively, and no significant difference in EGFR (P = 0.59) expression, with the TNM stage of EC, which suggested that ERCC1 and p53 could be potential markers for the TNM stage of EC. We also observed a significant increase in ERCC1 expression, and decrease in p53 and EGFR expression, in EC-9706 cells treated with SNX-2112 (P < 0.05), indicating the regulation of EC by SNX-2112. Furthermore, SNX-2112 treatment induced a significant decrease in the proliferation of EC-9706, which confirmed the function of SNX-2112. In summary, SNX-2112 inhibits the proliferation of EC cells by regulating the expression of ERCC1, EGFR, and p53.

show abstract

Activation of Egr-1 Expression in Astrocytes by HIV-1 Tat: New Insights into Astrocyte-Mediated Tat Neurotoxicity

Cited by 39 publications

References 62 publications

Role of Sigma Receptor in Cocaine-Mediated Induction of Glial Fibrillary Acidic Protein: Implications for HAND

Role of Sigma Receptor in Cocaine-Mediated Induction of Glial Fibrillary Acidic Protein: Implications for HAND

HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity

Effect of SNX-2112 on proliferation of esophageal cancer cells via regulation of excision repair cross-complementing 1, epidermal growth factor receptor, and p53 expression

Contact Info

Product

Resources

About