Myocardin inhibits cellular proliferation by inhibiting NF-kappaB(p65)-dependent cell cycle progression.
We previously reported the importance of the serum response factor (SRF) cofactor myocardin in controlling muscle gene expression as well as the fundamental role for the inflammatory transcription factor NF-kappaB in governing cellular fate. Inactivation of myocardin has been implicated in malignant tumor growth. However, the underlying mechanism of myocardin regulation of cellular growth remains unclear. Here we show that NF-kappaB(p65) represses myocardin activation of cardiac and smooth muscle genes in a CArG-box-dependent manner. Consistent with their functional interaction, p65 directly interacts with myocardin and inhibits the formation of the myocardin/SRF/CArG ternary complex in vitro and in vivo. Conversely, myocardin decreases p65-mediated target gene activation by interfering with p65 DNA binding and abrogates LPS-induced TNF-alpha expression. Importantly, myocardin inhibits cellular proliferation by interfering with NF-kappaB-dependent cell-cycle regulation. Cumulatively, these findings identify a function for myocardin as an SRF-independent transcriptional repressor and cell-cycle regulator and provide a molecular mechanism by which interaction between NF-kappaB and myocardin plays a central role in modulating cellular proliferation and differentiation.
Tang
Ru-Hang
RH
Departments of Surgery and Cell and Developmental Biology, Carolina Cardiovascular Biology Center, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Zheng
Xi-Long
XL
Callis
Thomas E
TE
Stansfield
William E
WE
He
Jiayin
J
Baldwin
Albert S
AS
Wang
Da-Zhi
DZ
Selzman
Craig H
CH
D000818:Animals; D001011:Aorta; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032383:Myocytes, Cardiac; D032389:Myocytes, Smooth Muscle; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D051996:Transcription Factor RelA / Q000502:physiology*; D015533:Transcriptional Activation; D000099251:Myocardin
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D012097:Repressor Proteins; D026362:Serum Response Factor; D015534:Trans-Activators; D051996:Transcription Factor RelA; D000099251:Myocardin; C077048:Hnrnpab protein, mouse