IGF-1 induces Pin1 expression in promoting cell cycle S-phase entry

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Research

Background:

• Insulin-like growth factor I (IGF-1) is a mitogen implicated in cancer progression.
• Prolyl isomerase Pin1 regulates cell cycle via phosphorylated Ser/Thr-Pro motifs.
• Pin1 knockout MEF cells show defects in serum-stimulated cell cycle re-entry.

Purpose of the Study:

• To investigate the role of Pin1 in IGF-1-mediated cell cycle progression.
• To elucidate the signaling pathways involved in IGF-1-induced Pin1 expression.
• To determine the impact of Pin1 on cyclin D1 and RB phosphorylation.

Main Methods:

• Utilized Pin1 knockout mouse embryo fibroblast (MEF) cells.
• Stimulated cells with IGF-1 and monitored cell cycle entry.
• Investigated signaling pathways using PI3K and MAP kinase inhibitors (LY294002, PD098059).
• Assessed protein expression of Pin1, cyclin D1, and RB phosphorylation.
• Restored Pin1 expression using adenovirus in knockout cells.

Main Results:

• Pin1 knockout MEF cells exhibited delayed S-phase entry upon IGF-1 stimulation.
• IGF-1 induced Pin1 expression, correlating with cyclin D1 and RB phosphorylation in breast cancer cells.
• IGF-1-induced Pin1 upregulation was mediated by PI3K and MAP kinase pathways.
• Cyclin D1 expression and RB phosphorylation were reduced in Pin1 knockout cells.
• Reintroduction of Pin1 restored cyclin D1 expression and RB phosphorylation.

Conclusions:

• IGF-1's mitogenic function is partly mediated by Pin1 induction.
• Pin1 stimulates cyclin D1 expression and RB phosphorylation, facilitating G0/G1-S transition.
• The IGF-1/Pin1 axis represents a potential target for cancer therapy.