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Analysis of Cell Cycle Position in Mammalian Cells
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p18INK4c and p27KIP1 are required for cell cycle arrest of differentiated myotubes

Terri K Myers1, Sébastien E Andreuzza, David S Franklin

  • 1Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.

Experimental Cell Research
|October 12, 2004
PubMed

Insights

Myogenic differentiation involves cell cycle arrest, regulated by inhibitors like p18 and p27. Loss of both p18 and p27 allows myotubes to re-enter the cell cycle, but terminal arrest still requires other factors.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Background:

  • Myogenic differentiation is a complex process involving irreversible cell cycle withdrawal and apoptosis resistance.
  • Cyclin-dependent kinase inhibitors, including p18, p21, and p27, play crucial roles in regulating these events.
  • Understanding the specific roles of these inhibitors is key to comprehending muscle development and regeneration.

Purpose of the Study:

  • To investigate the necessity of p18, p21, and p27 in initiating and maintaining cell cycle arrest in myotubes during differentiation and upon restimulation.
  • To determine the specific contributions of each inhibitor in preventing myotube proliferation and maintaining terminal differentiation.

Main Methods:

  • Utilized knockout mouse models lacking specific cyclin-dependent kinase inhibitors (p18, p21, p27).
  • Cultured multinucleated myotubes under differentiation conditions and restimulated with mitogenic signals.
  • Assessed cell cycle reentry, DNA synthesis, proliferation, and apoptosis using various molecular and cellular assays.

Main Results:

  • Myotubes lacking p27 (p27-/-) or both p18 and p27 (p18-/-p27-/-) showed low-frequency cell cycle reentry and DNA synthesis during differentiation.
  • p18-/-p27-/- myotubes exhibited significantly greater escape from cell cycle arrest compared to p27-/- myotubes upon mitogenic stimulation.
  • While p18 and p27 are essential for initiating arrest, another inhibitor is required for maintaining terminal arrest, as p18-/-p21-/- and p21-/-p27-/- myotubes remained arrested.
  • Restimulated p18-/-p27-/- myotubes showed nuclei in all cell cycle phases, with some rearresting in S or G2 phase, and increased apoptosis without specific cell cycle phase targeting.

Conclusions:

  • p18 and p27 collaborate to initiate and maintain G0 arrest during myogenic differentiation.
  • A third, unidentified cell cycle inhibitor works with p18 and p27 to ensure terminal cell cycle arrest in myotubes.
  • The combined expression levels of p18, p27, and this other inhibitor dictate the postmitotic state of myotube nuclei.

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