Open AccessMyocardin inhibits cellular proliferation by inhibiting NF-κB(p65)-dependent cell cycle progression
Author(s) -
Ruhang Tang,
Xi-Long Zheng,
Thomas E. Callis,
William E. Stansfield,
Jia-Yin He,
Albert S. Baldwin,
Da Zhi Wang,
Craig H. Selzman
Publication year - 2008
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0705842105
Subject(s) - myocardin , serum response factor , microbiology and biotechnology , repressor , cell growth , biology , cell cycle , transcription factor , regulation of gene expression , chemistry , cell , gene , genetics
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-κB 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-κB(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 complexin vitro andin vivo . Conversely, myocardin decreases p65-mediated target gene activation by interfering with p65 DNA binding and abrogates LPS-induced TNF-α expression. Importantly, myocardin inhibits cellular proliferation by interfering with NF-κB-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-κB and myocardin plays a central role in modulating cellular proliferation and differentiation.