title: Methamphetamine and HIV-1 Tat down regulate β-catenin signaling: implications for methampetamine abuse and HIV-1 co-morbidity.
abstract: Methamphetamine (Meth) abuse exacerbates HIV-1-associated neurocognitive disorders (HAND). The underlying mechanism for this effect is not entirely clear but likely involves cooperation between Meth and HIV-1 virotoxins, such as the transactivator of transcription, Tat. HIV-1 Tat mediates damage in the CNS by inducing inflammatory processes including astrogliosis. Wnt/β-catenin signaling regulates survival processes for both neurons and astrocytes. Here, we evaluated the impact of Meth on the Wnt/β-catenin pathway in astrocytes transfected with Tat. Meth and Tat downregulated Wnt/β-catenin signaling by >50%, as measured by TOPflash reporter activity in both an astrocytoma cell line and primary human fetal astrocytes. Meth and Tat also downregulated LEF-1 transcript by >30%. LEF-1 is a key partner of β-catenin to regulate cognate gene expression. Interestingly, estrogen, which induces β-catenin signaling in a cell-type specific manner, at physiological concentrations of 1.5 and 3 nM normalized individual Meth and Tat effects on β-catenin signaling but not their combined effects. These findings suggest that Meth and Tat likely exert different mechanisms to mediate down regulation of β-catenin signaling. The consequences of which may contribute to the pathophysiologic effects of HIV-1 and Meth co-morbidity in the CNS.
authors: Department of Immunology/Microbiology, Rush University Medical Center, 1735 W. Harrison Street, 614 Cohn, Chicago, IL 60612, USA.
authors: Amit
authors: A
authors: Sharma
authors: Xiu-Ti
authors: XT
authors: Hu
authors: T Celeste
authors: TC
authors: Napier
authors: Lena
authors: L
authors: Al-Harthi
mesh_terms: D015526:AIDS Dementia Complex / Q000378:metabolism / Q000821:virology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D015897:Comorbidity; D015536:Down-Regulation; D015658:HIV Infections / Q000453:epidemiology* / Q000821:virology; D015497:HIV-1; D006801:Humans; D013287:Illicit Drugs / Q000494:pharmacology*; D008694:Methamphetamine / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D019966:Substance-Related Disorders / Q000453:epidemiology* / Q000821:virology; D051176:beta Catenin / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D000697:Central Nervous System Stimulants; D013287:Illicit Drugs; D051176:beta Catenin; D054322:tat Gene Products, Human Immunodeficiency Virus; D008694:Methamphetamine