The tumour suppressor protein, p53, is involved in the activation of the apoptotic cascade by Δ9-tetrahydrocannabinol in cultured cortical neurons

Eric J. Downer, Aoife Gowran, Áine C. Murphy, Veronica A. Campbell

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Cannabis is the most commonly used illegal drug of abuse in Western society. Δ9-tetrahydrocannabinol, the psychoactive ingredient of marijuana, regulates a variety of neuronal processes including neurotransmitter release and synaptic transmission. An increasing body of evidence suggests that cannabinoids play a key role in the regulation of neuronal viability. In cortical neurons tetrahydrocannabinol has a neurodegenerative effect, the mechanisms of which are poorly understood, but involve the cannabinoid receptor subtype, CB1. In this study we report that tetrahydrocannabinol (5 μM) evokes a rapid phosphorylation, and thus activation, of the tumour suppressor protein, p53, in a manner involving the cannabinoid CB1 receptor, and the stress-activated protein kinase, c-jun N-terminal kinase, in cultured cortical neurons. Tetrahydrocannabinol increased expression of the p53-transcriptional target, Bax and promoted Bcl phosphorylation. These events were abolished by the p53 inhibitor, pifithrin-α (100 nM). The tetrahydrocannabinol-induced activation of the pro-apoptotic cysteine protease, caspase-3, and DNA fragmentation was also blocked by pifithrin-α. A siRNA knockdown of p53 further verified the role of p53 in tetrahydrocannabinol-induced apoptosis. This study demonstrates a novel cannabinoid signalling pathway involving p53 that culminates in neuronal apoptosis.

Original languageEnglish
Pages (from-to)57-65
Number of pages9
JournalEuropean Journal of Pharmacology
Volume564
Issue number1-3
DOIs
Publication statusPublished - Jun 14 2007

Fingerprint

Tumor Suppressor Protein p53
Dronabinol
Neurons
Cannabinoid Receptor CB1
Cannabinoids
Cannabis
Phosphorylation
Apoptosis
Cysteine Proteases
JNK Mitogen-Activated Protein Kinases
Street Drugs
DNA Fragmentation
Heat-Shock Proteins
Synaptic Transmission
Caspase 3
Protein Kinases
Small Interfering RNA
Neurotransmitter Agents

Keywords

  • Apoptosis
  • p53
  • Tetrahydrocannabinol

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

The tumour suppressor protein, p53, is involved in the activation of the apoptotic cascade by Δ9-tetrahydrocannabinol in cultured cortical neurons. / Downer, Eric J.; Gowran, Aoife; Murphy, Áine C.; Campbell, Veronica A.

In: European Journal of Pharmacology, Vol. 564, No. 1-3, 14.06.2007, p. 57-65.

Research output: Contribution to journalArticle

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