journal club meeting 20.12.2014
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Transcript of journal club meeting 20.12.2014
Rac is the actual regulator of RhoA!
Tiam1 and miR-21 are the main
regulators of Rac
FTase regulates RhoA?
Points to be addressed
Small GTPases proteins are involved in cell motility
RhoA Rac Cdc42
Membrane
ruffles and
lamellipodia
filopodia Stress fibers
and focal
adhesion
Endothelial Cell Migration During Angiogenesis. Circ Res. 2007;100:782-794
What is the relation between Rho and Rac?
Jacobson, Dudek, Birukov, et al. Simvastatin Alters EC Function and Gene Expression Am. J. Respir. Cell Mol. Biol. 2004
Simvastatin mode of Rho/Rac regulation..!
Ruqin Kou et al. Regulation of Rac1 by simvastatin in endothelial cells: differential roles of AMP-activated protein kinase and calmodulin-dependent kinase kinase-beta. J Biol Chem. 2009 May 29; 284
Statin
increases Rac
activity
Mevalonate and
isopernoids
decrease Rac
activity
Data Normalized against beta actin and calibrated against Untreated control cells
0
0.5
1
1.5
2
2.5
Simv treated cells
CCL17 treated cells Fold
ch
ange
s
Rac1 mRNA
RhoA mRNA
Simvastatin
increases Rac and
decreases RhoA
Reciprocal relation
ship!
% o
f m
igra
ted
cel
ls
__ Vehicle 10 20
*
*
#
CCL17+FTI-277 µM
Pirkko L. Harkonen et al. Inhibition of GGTase-I and FTase disrupts cytoskeletal organization of human PC-3 prostate cancer cells. Cell Biol. Int. (2010) 34, 815–826
What about FTi-277?
RhoA mRNA
Journal of the National Cancer Institute feb.2013
Serum miR-21 as a Diagnostic and Prognostic Biomarkerin Colorectal Cancer
Charisa et as. miR-21 and miR-31 Converge on TIAM1 to Regulate Migration and Invasion of Colon Carcinoma Cells. J Biol Chem. 2010 November 12; 285
Upregulation of miR-21 increases migration and invasion of colon cancer cells
Charisa et as. miR-21 and miR-31 Converge on TIAM1 to Regulate Migration and Invasion of Colon Carcinoma Cells. J Biol Chem. 2010 November 12; 285
Rho/Rac Ratio
If RhoA ˃ Rac Active migration
If Rac ˃ RhoA Active invasion or ?
RhoA ᾱ 1/Rac
miR-21 Tiam1 Rac RhoA
Cell migration control?
FTase
?
In conclusion, our novel findings suggest that Rac1 signaling is a key component in the pathophysiology of acute lung injury triggered by streptococcal M1 protein. Inhibition of Rac1 activity reduces M1 protein-provoked neutrophil infiltration in the lung via inhibition of CXC chemokine formation in alveolar macrophages. These results suggest that targeting Rac1 signaling might be a useful approach in order to protect respiratory function in streptococcal infections.
Streptococcal M1 Protein Triggers Farnesyltransferase-Dependent Formation of CXC Chemokines in Alveolar Macrophages and Neutrophil Infiltration of the Lungs Songen Zhanga, Milladur Rahmana, Su Zhanga, Bengt Jeppssona, Heiko Herwaldb and Henrik Thorlaciusa Our novel findings demonstrate that farnesyltransferase is an important regulator of neutrophil-mediated acute lung injury triggered by streptococcal M1protein. Moreover, we demonstrate that inhibition of farnesyltransferase abolishes the macrophage dependent generation of CXC chemokines in response toM1protein challenge. Thus, we conclude that these farnesyltransferasedependent mechanisms may, at least in part, help to clarify the beneficial effects exerted by statins and that targeting farnesyltransferase activity might be useful in order to protect against respiratory failure in streptococcal infections.
Targeting Rac1 Signaling Inhibits Streptococcal M1 Protein-Induced CXC Chemokine Formation, Neutrophil Infiltration and Lung Injury Songen Zhang1, Milladur Rahman1, Su Zhang1, Lei Song1, Heiko Herwald2, Henrik Thorlacius