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Regulation of urokinase receptor transcription by Ras- and Rho-family GTPases
1School of Biomedical Sciences, Queen's Medical Centre, Nottingham, NG7 2UH, United Kingdom.
Abstract:
How cell adhesion is coordinated with extracellular proteolysis is a key question in understanding cell migration. Potentially, the small GTP-binding proteins that affect actin organisation and signal transduction may also regulate the expression of genes associated with extracellular proteolysis. We investigated the ability of Ras, Rac-1, Cdc42Hs, and RhoA to regulate transcription from the1.55-kb promoter region of the human urokinase plasminogen activator receptor (uPAR) gene. Constitutively active V12 H-Ras and Rho-A stimulated uPAR transcription while Cdc42Hs and Rac-1 did not. The use of Ras effector-loop mutants indicated that signalling via multiple Ras-effectors is necessary for the maximum activation of transcription.
Insights
Ras and RhoA proteins regulate urokinase plasminogen activator receptor (uPAR) gene transcription, crucial for cell migration. This study reveals how small GTP-binding proteins coordinate cell adhesion with extracellular proteolysis.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Cell migration relies on coordinating cell adhesion with extracellular proteolysis.
- Small GTP-binding proteins influence actin organization and signal transduction.
- These proteins may regulate genes involved in extracellular proteolysis.
Purpose of the Study:
- To investigate the role of Ras, Rac-1, Cdc42Hs, and RhoA in regulating transcription of the human urokinase plasminogen activator receptor (uPAR) gene.
- To understand the signaling pathways involved in uPAR gene regulation by small GTP-binding proteins.
Main Methods:
- Investigated transcription from the 1.55-kb promoter region of the human uPAR gene.
- Utilized constitutively active forms of Ras, RhoA, Cdc42Hs, and Rac-1.
- Employed Ras effector-loop mutants to dissect signaling pathways.
Main Results:
- Constitutively active V12 H-Ras and Rho-A significantly stimulated uPAR transcription.
- Cdc42Hs and Rac-1 did not show a significant effect on uPAR transcription.
- Signaling through multiple Ras-effectors is required for maximal uPAR transcription activation.
Conclusions:
- Ras and RhoA play a key role in regulating uPAR gene transcription.
- The findings provide insights into the molecular mechanisms coordinating cell adhesion and proteolysis during cell migration.
- Understanding these pathways is crucial for comprehending cell motility and related processes.