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Role of ?-catenin and TCF/LEF family members in transcriptional activity of HIV in astrocytes.

ABSTRACT: The Wnt/?-catenin pathway is involved in diverse cell functions governing development and disease. ?-Catenin, a central mediator of this pathway, binds to members of the TCF/LEF family of transcription factors to modulate hundreds of genes. Active Wnt/?-catenin/TCF-4 signaling plays a significant role in repression of HIV-1 replication in multiple cell targets, including astrocytes. To determine the mechanism by which active ?-catenin/TCF-4 leads to inhibition of HIV replication, we knocked down ?-catenin or TCF/LEF members in primary astrocytes and astrocytomas transiently transfected with an HIV long terminal repeat (LTR)-luciferase reporter that contained an integrated copy of the HIV LTR-luciferase construct. Knockdown of either ?-catenin or TCF-4 induced LTR activity by 2- to 3-fold under both the episomal and integrated conditions. This knockdown also increased presence of serine 2-phosphorylated RNA polymerase II (Pol II) on the HIV LTR as well as enhanced its processivity. Knockdown of ?-catenin/TCF-4 also impacted tethering of other transcription factors on the HIV promoter. Specifically, knockdown of TCF-4 enhanced binding of C/EBP?, C/EBP?, and NF-?B to the HIV LTR, while ?-catenin knockdown increased binding of C/EBP? and C/EBP? but had no effect on NF-?B. Approximately 150 genes in astrocytes were impacted by ?-catenin knockdown, including genes involved in inflammation/immunity, uptake/transport, vesicular transport/exocytosis, apoptosis/cellular stress, and cytoskeleton/trafficking. These findings indicate that modulation of the ?-catenin/TCF-4 axis impacts the basal level of HIV transcription in astrocytes, which may drive low level/persistent HIV in astrocytes that can contribute to ongoing neuroinflammation, and this axis also has profound effects on astrocyte biology.

SUBMITTER: Narasipura SD

PROVIDER: S-EPMC3302377 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Role of β-catenin and TCF/LEF family members in transcriptional activity of HIV in astrocytes.

Narasipura Srinivas D SD Henderson Lisa J LJ Fu Sidney W SW Chen Liang L Kashanchi Fatah F Al-Harthi Lena L

Journal of virology 20111207 4

The Wnt/β-catenin pathway is involved in diverse cell functions governing development and disease. β-Catenin, a central mediator of this pathway, binds to members of the TCF/LEF family of transcription factors to modulate hundreds of genes. Active Wnt/β-catenin/TCF-4 signaling plays a significant role in repression of HIV-1 replication in multiple cell targets, including astrocytes. To determine the mechanism by which active β-catenin/TCF-4 leads to inhibition of HIV replication, we knocked down ...[more]

PMID: 22156527

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Dataset Information

Role of ?-catenin and TCF/LEF family members in transcriptional activity of HIV in astrocytes.

Publications

Role of β-catenin and TCF/LEF family members in transcriptional activity of HIV in astrocytes.

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