Repression of smooth muscle differentiation by a novel high mobility group box-containing protein, HMG2L1.
The molecular mechanisms regulating smooth muscle-specific gene expression during smooth muscle development are poorly understood. Myocardin is an extraordinarily powerful cofactor of serum response factor (SRF) that stimulates expression of smooth muscle-specific genes. In an effort to search for proteins that regulate myocardin function, we identified a novel HMG box-containing protein HMG2L1 (high mobility group 2 like 1). We found that HMG2L1 expression is correlated with the smooth muscle cell (SMC) synthetic phenotype. Overexpression of HMG2L1 in SMCs down-regulated smooth muscle marker expression. Conversely, depletion of endogenous HMG2L1 in SMCs increases smooth muscle-specific gene expression. Furthermore, we found HMG2L1 specifically abrogates myocardin-induced activation of smooth muscle-specific genes. By GST pulldown assays, the interaction domains between HMG2L1 and myocardin were mapped to the N termini of each of the proteins. Finally, we demonstrated that HMG2L1 abrogates myocardin function through disrupting its binding to SRF and abolishing SRF-myocardin complex binding to the promoters of smooth muscle-specific genes. This study provides the first evidence of this novel HMG2L1 molecule playing an important role in attenuating smooth muscle differentiation.
Zhou
Jiliang
J
Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208, USA. zhouj1@mail.amc.edu
Hu
Guoqing
G
Wang
Xiaobo
X
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D024261:HMGB2 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009130:Muscle, Smooth / Q000254:growth & development; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D009928:Organ Specificity; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D026362:Serum Response Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation; D000099251:Myocardin
D024261:HMGB2 Protein; D009687:Nuclear Proteins; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000099251:Myocardin; C527734:HMGXB4 protein, human; C503315:myocardin-related transcription factor B, mouse