Journal article
Smooth muscle cell-specific transcription is regulated by nuclear localization of the myocardin-related transcription factors
American journal of physiology. Heart and circulatory physiology, Vol.292(2), pp.H1170-1180
02/2007
DOI: 10.1152/ajpheart.00864.2006
PMID: 16997888
Abstract
On the basis of our previous studies on RhoA signaling in smooth muscle cells (SMC), we hypothesized that RhoA-mediated nuclear translocalization of the myocardin-related transcription factors (MRTFs) was important for regulating SMC phenotype. MRTF-A protein and MRTF-B message were detected in aortic SMC and in many adult mouse organs that contain a large SMC component. Both MRTFs upregulated SMC-specific promoter activity as well as endogenous SM22alpha expression in multipotential 10T1/2 cells, although to a lesser extent than myocardin. We used enhanced green fluorescent protein (EGFP) fusion proteins to demonstrate that the myocardin factors have dramatically different localization patterns and that the stimulation of SMC-specific transcription by certain RhoA-dependent agonists was likely mediated by increased nuclear translocation of the MRTFs. Importantly, a dominant-negative form of MRTF-A (DeltaB1/B2) that traps endogenous MRTFs in the cytoplasm inhibited the SM alpha-actin, SM22alpha, and SM myosin heavy chain promoters in SMC and attenuated the effects of sphingosine 1-phosphate and transforming growth factor (TGF)-beta on SMC-specific transcription. Our data confirmed the importance of the NH(2)-terminal RPEL domains for regulating MRTF localization, but our analysis of MRTF-A/myocardin chimeras and myocardin RPEL2 mutations indicated that the myocardin B1/B2 region can override this signal. Gel shift assays demonstrated that myocardin factor activity correlated well with ternary complex formation at the SM alpha-actin CArGs and that MRTF-serum response factor interactions were partially dependent on CArG sequence. Taken together, our results indicate that the MRTFs regulate SMC-specific gene expression in at least some SMC subtypes and that regulation of MRTF nuclear localization may be important for the effects of selected agonists on SMC phenotype.
Details
- Title: Subtitle
- Smooth muscle cell-specific transcription is regulated by nuclear localization of the myocardin-related transcription factors
- Creators
- Jeremiah S Hinson - Department of Pathology and Laboratory Medicine and the Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina 27599, USAMatthew D MedlinKashelle LockmanJoan M TaylorChristopher P Mack
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Heart and circulatory physiology, Vol.292(2), pp.H1170-1180
- Publisher
- United States
- DOI
- 10.1152/ajpheart.00864.2006
- PMID
- 16997888
- ISSN
- 0363-6135
- eISSN
- 1522-1539
- Grant note
- HL-070953 / NHLBI NIH HHS R01 HL081844 / NHLBI NIH HHS HL-081844 / NHLBI NIH HHS R01 HL071054 / NHLBI NIH HHS HL-071054 / NHLBI NIH HHS
- Language
- English
- Date published
- 02/2007
- Academic Unit
- Pharmacy Practice and Science; Office of Consultation and Research in Medical Education; Internal Medicine
- Record Identifier
- 9984065315202771
Metrics
20 Record Views