Involvement of p300 in constitutive and HIV-1 Tat-activated expression of glial fibrillary acidic protein in astrocytes.
HIV-1 Tat protein is an important pathogenic factor in HIV-1-associated neurological diseases. One hallmark of HIV-1 infection of the central nervous system (CNS) is astrocytosis, which is characterized by elevated glial fibrillary acidic protein (GFAP) expression in astrocytes. We have shown that Tat activates GFAP expression in astrocytes [Zhou et al., (2004) Mol Cell Neurosci 27:296-305] and that GFAP is an important regulator of Tat neurotoxicity [Zou et al., (2007) Am J Pathol 171:1293-1935]. However, the underlying mechanisms for Tat-mediated GFAP up-regulation are not understood. In this study, we reported concurrent up-regulation of adenovirus E1a-associated 300 kDa protein p300 and GFAP in Tat-expressing human astrocytoma cells and primary astrocytes. We showed that p300 was indeed induced by Tat expression and HIV-1 infection and that the induction occurred at the transcriptional level through the cis-acting elements of early growth response 1 (egr-1) within its promoter. Using siRNA, we further showed that p300 regulated both constitutive and Tat-mediated GFAP expression. Moreover, we showed that ectopic expression of p300 potentiated Tat transactivation activity and increased proliferation of HIV-1-infected astrocytes, but had little effect on HIV-1 replication in these cells. Taken together, these results demonstrate for the first time that Tat is a positive regulator of p300 expression, which in turn regulates GFAP expression, and suggest that the Tat-Egr-1-p300-GFAP axis likely contributes to Tat neurotoxicity and predisposes astrocytes to be an HIV-1 sanctuary in the CNS.
Zou
Wei
W
Department of Internal Medicine, Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Wang
Zhenyuan
Z
Liu
Ying
Y
Fan
Yan
Y
Zhou
Betty Y
BY
Yang
X Frank
XF
He
Johnny J
JJ
D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D015658:HIV Infections / Q000378:metabolism; D006801:Humans; D034741:RNA, Small Interfering / Q000494:pharmacology; D013778:Tetrazolium Salts; D013844:Thiazoles; D013936:Thymidine / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014316:Tritium / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D001616:beta-Galactosidase / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000009:adverse effects*
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D005904:Glial Fibrillary Acidic Protein; D034741:RNA, Small Interfering; D013778:Tetrazolium Salts; D013844:Thiazoles; D054322:tat Gene Products, Human Immunodeficiency Virus; D014316:Tritium; D049452:Green Fluorescent Proteins; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D001616:beta-Galactosidase; C022616:thiazolyl blue; D013936:Thymidine