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Research Interests:
The general focus of the laboratory is to utilize regenerating liver as a NORMAL model for understanding how the plasminogen activator system contributes to the development of diseases such as CANCER.
In the rat, liver regeneration is at least partially dependent upon a growth factor known as hepatocyte growth factor (HGF). HGF can be activated in vitro by the urokinase-type and tissue-type plasminogen activators (u-PA and t-PA); however, in vivo only u-PA seems to be important for compensatory liver regeneration in the rat. These proteins are part of a "system" which includes selected receptors (for example the u-PA receptors, u-PAR and LRP), inhibitors (for example, the type 1 plasminogen activator inhibitor or PAI-1), and substrates (such as plasminogen (Plg) and HGF). All if the members of this "system" have been implicated in cancer biology in some way or another; however, their roles in contributing to the cancer phenotype remain unclear. One way to approach this problem is to study these proteins in a normal model of tissue regeneration such as regenerating liver.
In order to further elucidate the role of this system in tissue regeneration, mice were obtained which have deletions in the genes encoding u-PA, t-PA, PAI-1, u-PAR and Plg (knockout mice). Due to the redundancy of the system, double knockouts were bred, combining a deficiency of u-PAR and either t-PA or u-PA. The livers from the single and double knockouts are currently being studied in order to determine exactly how the different proteins contribute to compensatory liver regeneration. Additionally, as these same proteins are involved in the growth of many tissues, studies are in progress to determine the effect of deleting these genes during brain development. Finally, a serum-free rat hepatocyte culture model is being utilized to examine the system components that contribute to cleavage of HGF versus Plg.
Selected Publications:
View Dr. Mars' publications on PubMed.
Hu, K., Yang, J., Tanaka, S., Gonias, S.L., Mars, W.M., and Liu, Y. Tissue-type plasminogen activator acts as a cytokine that triggers intracellular signal transduction and induces matrix metalloproteinase-9 gene expression. J. Biol. Chem. 281, 2120-2127, (2006).
Lagoa, C.E., Vodovotz, Y., Stolz, D.B. Lluillier, F., McCloskey, C., Gallo, D., Yang, R., Ustinova, E., Fink, M., Billiar, T.R. and Mars, W.M. Contribution of type 1 plasminogen activator inhibitor (PAI-1) to hepatic injury during hemorrhagic shock. Hepatology 42, 390-399 (2005).
Mars, W.M. Jo, M. and Gonias, S.L. Activation of Hepatocyte Growth Factor by urokinase-type plasminogen activator is ionic strength-dependent. Biochem. J 390, 311-315 (2005).
Schoedel KE, Tyner VZ, Kim TH, Michalopoulos GK, Mars WM. HGF, MET, and matrix-related proteases in hepatocellular carcinoma, fibrolamellar variant, cirrhotic and normal liver. Mod Pathol. 2003 Jan;16(1):14-21.
Yang J, Shultz RW, Mars WM, Wegner RE, Li Y, Dai C, Nejak K, Liu Y. Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy. J Clin Invest. 2002 Nov;110(10):1525-38.
Monga SP, Mars WM, Pediaditakis P, Bell A, Mule K, Bowen WC, Wang X, Zarnegar R, Michalopoulos GK. Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. Cancer Res. 2002 Apr 1;62(7):2064-71.
Pediaditakis P, Monga SP, Mars WM, Michalopoulos GK. Differential mitogenic effects of single chain hepatocyte growth factor (HGF)/scatter factor and HGF/NK1 following cleavage by factor Xa. J Biol Chem. 2002 Apr 19;277(16):14109-15.
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