LMO7 mediates cell-specific activation of the Rho-myocardin-related transcription factor-serum response factor pathway and plays an important role in breast cancer cell migration.

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.

• 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)

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

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)