Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin

Dev Cell. 2005 Aug;9(2):261-70. doi: 10.1016/j.devcel.2005.05.017.


Smooth muscle cells (SMCs) modulate their phenotype between proliferative and differentiated states in response to physiological and pathological cues. Insulin-like growth factor-I stimulates differentiation of SMCs by activating phosphoinositide-3-kinase (PI3K)-Akt signaling. Foxo forkhead transcription factors act as downstream targets of Akt and are inactivated through phosphorylation by Akt. We show that Foxo4 represses SMC differentiation by interacting with and inhibiting the activity of myocardin, a transcriptional coactivator of smooth muscle genes. PI3K/Akt signaling promotes SMC differentiation, at least in part, by stimulating nuclear export of Foxo4, thereby releasing myocardin from its inhibitory influence. Accordingly, reduction of Foxo4 expression in SMCs by siRNA enhances myocardin activity and SMC differentiation. We conclude that signal-dependent interaction of Foxo4 with myocardin couples extracellular signals with the transcriptional program for SMC differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Carotid Arteries / cytology
  • Carotid Arteries / metabolism
  • Cell Differentiation
  • Cell Line
  • Chlorocebus aethiops
  • Forkhead Transcription Factors
  • Male
  • Mice
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / metabolism*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phenotype
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Protein Binding
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Small Interfering / genetics
  • Rats
  • Signal Transduction
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tunica Intima / cytology
  • Tunica Intima / metabolism
  • Up-Regulation


  • Forkhead Transcription Factors
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Trans-Activators
  • Transcription Factors
  • myocardin
  • Protein Kinases
  • serum response factor kinase
  • Akt1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt