Somatostatin inhibits AP-1 function via multiple protein phosphatases

Area of Science:

• Endocrinology
• Molecular Biology
• Cell Biology

Background:

• Somatostatin exhibits widespread inhibitory actions, potentially by suppressing immediate early genes like c-fos and c-jun.
• The products of c-fos and c-jun form the activator protein 1 (AP-1) transcription factor, induced by phorbol esters.

Purpose of the Study:

• To investigate the precise mechanisms through which somatostatin inhibits immediate early gene expression.
• To elucidate the role of protein phosphatases and specific somatostatin receptor subtypes in this inhibitory pathway.

Main Methods:

• Utilized a rat pituitary adenoma cell line (GH3) expressing multiple somatostatin receptor subtypes.
• Assessed AP-1 binding and transcriptional activity following phorbol ester (TPA) stimulation and somatostatin analogue (octreotide) treatment.
• Investigated the impact of phosphatase inhibitors (sodium orthovanadate, okadaic acid) and pertussis toxin on somatostatin's effects.

Main Results:

• Octreotide inhibited TPA-stimulated AP-1 binding and transcriptional activity by 40-70% in GH3 cells.
• The inhibitory effect of octreotide was abolished by phosphatase inhibitors.
• Octreotide inhibited TPA-stimulated GH3 cell proliferation, an effect reversed by pertussis toxin pretreatment.

Conclusions:

• Somatostatin inhibits immediate early gene expression and AP-1 binding/transcriptional activity through protein phosphatases.
• This somatostatin-mediated inhibition is sensitive to pertussis toxin, implicating G protein-coupled receptors.
• The findings suggest a novel mechanism by which somatostatin inhibits cellular proliferation via AP-1 pathway modulation.