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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

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Abstract

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.

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Abbreviations

HIV-1:

Human Immunodeficiency Virus-1

NPC:

Neural precursor cell

ERK1/2:

Extracellular signal-regulated kinase ½

IFNγ:

Interferon-γ

Stat:

Signal Transducer and Activator of Transcription

Sox2:

SRY (sex determining region-Y)-box2

HAND:

HIV-associated neurocognitive disorders

BrdU:

Bromodeoxyuridine

EGFR:

Epidermal growth factor receptor

FITC:

Fluorescein isothiocyanate

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

EthD-1:

Ethidium homodimer-1

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

CDK:

Cyclin dependent kinase

esiRNA:

Endoribonuclease-prepared short interfering RNA

EGFP:

Enhanced green fluorescent protein

MEK1/2:

Mitogen activated protein kinase kinase

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Acknowledgments

Technical assistance from Mr. Durga Lal Meena and Mr. Naushad Alam during the study, Senior Research Fellowship to SM, Project Assistantship to RS and core funding to PS laboratory from NBRC, Manesar and Department of Biotechnology, New Delhi, are greatly acknowledged.

Conflict of Interest

The authors declare that no conflicts of interest exist.

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Author notes

  1. Rinki Saha

    Present address: Sagol Department of Neurobiology and Ethology, University of Haifa, Haifa, Israel

Authors and Affiliations

  1. Cellular and Molecular Neuroscience, National Brain Research Centre (NBRC), NH-8, Nainwal Road, Manesar, Gurgaon, Haryana, 122051, India

    Shaily Malik, Rinki Saha & Pankaj Seth

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  1. Shaily Malik
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Correspondence to Pankaj Seth.

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Malik, S., Saha, R. & Seth, P. 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. J Neuroimmune Pharmacol 9, 340–353 (2014). https://doi.org/10.1007/s11481-014-9523-7

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