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.
Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208, USA. zhouj1@mail.amc.edu
Jiliang
J
Zhou
Guoqing
G
Hu
Xiaobo
X
Wang
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