Abstract |
Serum response factor (SRF) is a ubiquitously expressed transcription factor that regulates cell-specific functions such as muscle development and breast cancer metastasis. The myocardin-related transcription factors (MRTFs), which are transcriptional coactivators mediating cell-specific functions of SRF, are also ubiquitously expressed. How MRTFs and SRF drive cell-specific transcription is still not fully understood. Here we show that LIM domain only 7 (LMO7) is a cell-specific regulator of MRTFs and plays an important role in breast cancer cell migration. LMO7 activates MRTFs by relieving actin-mediated inhibition in a manner that requires, and is synergistic with, Rho GTPase. Whereas Rho is required for LMO7 to activate full-length MRTFs that have three RPEL actin-binding motifs, the disruption of individual actin-RPEL interactions is sufficient to eliminate the Rho dependency and to allow the strong Rho-independent function of LMO7. Mechanistically, we show that LMO7 colocalizes with F-actin and reduces the G-actin/ F-actin ratio via a Rho-independent mechanism. The knockdown of LMO7 in HeLa and MDA-MB-231 cells compromises both basal and Rho-stimulated MRTF activities and impairs the migration of MDA-MB-231 breast cancer cells. We also show that LMO7 is upregulated in the stroma of invasive breast carcinoma in a manner that correlates with the increased expression of SRF target genes that regulate muscle and actin cytoskeleton functions. Together, this study reveals a novel cell-specific mechanism regulating Rho-MRTF-SRF signaling and breast cancer cell migration and identifies a role for actin-RPEL interactions in integrating Rho and cell-specific signals to achieve both the synergistic and Rho-dependent activation of MRTFs.
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Authors | Qiande Hu, Chun Guo, Yali Li, Bruce J Aronow, Jinsong Zhang |
Journal | Molecular and cellular biology
(Mol Cell Biol)
Vol. 31
Issue 16
Pg. 3223-40
(Aug 2011)
ISSN: 1098-5549 [Electronic] United States |
PMID | 21670154
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Actins
- DNA-Binding Proteins
- Homeodomain Proteins
- LIM Domain Proteins
- LMO7 protein, human
- MRTFA protein, human
- Oncogene Proteins, Fusion
- Serum Response Factor
- Trans-Activators
- Transcription Factors
- rhoA GTP-Binding Protein
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Topics |
- Actins
(metabolism)
- Breast Neoplasms
(pathology)
- Cell Line, Tumor
- Cell Movement
- DNA-Binding Proteins
(metabolism)
- Female
- Homeodomain Proteins
(physiology)
- Humans
- LIM Domain Proteins
- Oncogene Proteins, Fusion
(metabolism)
- Organ Specificity
- Serum Response Factor
(metabolism)
- Signal Transduction
- Trans-Activators
- Transcription Factors
(physiology)
- Transcriptional Activation
- rhoA GTP-Binding Protein
(metabolism)
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