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PDGF-BB regulates p27 expression through ERK-dependent RNA turn-over in vascular smooth muscle cells

Kenji Sakakibara1, Kenji Kubota, Berhane Worku

  • 1Department of Surgery, Division of Vascular Surgery, Weill Medical College of Cornell University, New York, New York 10021, USA.

The Journal of Biological Chemistry
|May 17, 2005
PubMed

Insights

Platelet-derived growth factor BB (PDGF-BB) reduces p27 protein and mRNA in smooth muscle cells via ERK activation. This occurs through a posttranscriptional mechanism affecting mRNA stability, not gene activity.

Area of Science:

  • Vascular Biology
  • Cell Cycle Regulation
  • Molecular Mechanisms

Background:

  • p27 is a key regulator of cell cycle progression and is targeted by mitogenic signals during arterial injury.
  • Vascular smooth muscle cell proliferation is a hallmark of arterial injury and restenosis.

Purpose of the Study:

  • To investigate the role of ERK signaling in PDGF-BB-mediated regulation of p27 expression in vascular smooth muscle cells.
  • To elucidate the molecular mechanisms underlying p27 down-regulation by PDGF-BB.

Main Methods:

  • Primary rat aortic smooth muscle cells were treated with PDGF-BB.
  • ERK signaling pathway activation and inhibition were manipulated using specific inhibitors and constitutively active MEK.
  • p27 mRNA and protein levels were quantified.
  • p27 promoter activity and mRNA stability were assessed using reporter gene assays and half-life measurements.

Main Results:

  • PDGF-BB significantly reduced p27 protein and mRNA levels in a manner dependent on ERK activation.
  • Inhibition of ERK prevented PDGF-BB-induced p27 down-regulation, while MEK activation mimicked this effect.
  • PDGF-BB stimulation shortened p27 mRNA half-life without altering promoter activity, indicating a posttranscriptional regulation mechanism.
  • The 3'-untranslated region of p27 mRNA was identified as crucial for PDGF-BB-mediated regulation via ERK.

Conclusions:

  • PDGF-BB down-regulates p27 expression in vascular smooth muscle cells through an ERK-dependent posttranscriptional mechanism.
  • ERK signaling plays a critical role in controlling p27 mRNA stability in response to mitogenic stimuli.
  • These findings highlight a novel regulatory pathway impacting cell cycle control in vascular smooth muscle cells during injury.

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