Involvement of extracellular signal-regulated kinase (ERK1/2)-p53-p21 axis in mediating neural stem/progenitor cell cycle arrest in co-morbid HIV-drug abuse exposure.
Neurological complications in opioid abusing Human Immunodeficiency Virus-1 (HIV-1) patients suggest enhanced neurodegeneration as compared to non-drug abusing HIV-1 infected population. Neural precursor cells (NPCs), the multipotent cells of the mammalian brain, are susceptible to HIV-1 infection and as opiates also perturb their growth kinetics, detailed mechanistic studies for their co-morbid exposure are highly warranted. Using a well characterized in vitro model of human fetal brain-derived neural precursor cells, we investigated alterations in NPC properties at both acute and chronic durations. Chronic morphine and Tat treatment attenuated proliferation in NPCs, with cells stalled at G1-phase of the cell cycle. Furthermore HIV-Tat and morphine exposure increased activation of extracellular signal-regulated kinase-1/2 (ERK1/2), enhanced levels of p53 and p21, and decreased cyclin D1 and Akt levels in NPCs. Regulated by ERK1/2 and p53, p21 was found to be indispensible for Tat and morphine mediated cell cycle arrest. Our study elaborates on the cellular and molecular machinery in NPCs and provides significant mechanistic details into HIV-drug abuse co-morbidity that may have far reaching clinical consequences both in pediatric as well as adult neuroAIDS.
Cellular and Molecular Neuroscience, National Brain Research Centre (NBRC), NH-8, Nainwal Road, Manesar, Gurgaon, Haryana, 122051, India.
Shaily
S
Malik
Rinki
R
Saha
Pankaj
P
Seth
D051017:Apoptosis Regulatory Proteins / Q000633:toxicity; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D015897:Comorbidity; D053686:Fetal Stem Cells / Q000187:drug effects / Q000502:physiology; D015658:HIV Infections / Q000453:epidemiology / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D009020:Morphine / Q000633:toxicity; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000633:toxicity; D019966:Substance-Related Disorders / Q000453:epidemiology / Q000378:metabolism; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000633:toxicity
D051017:Apoptosis Regulatory Proteins; C512124:HIV-TAT-survivin (T34A) protein; D011993:Recombinant Fusion Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D054322:tat Gene Products, Human Immunodeficiency Virus; D009020:Morphine; D020741:rho GTP-Binding Proteins