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Research Interests:
The main focus of the Dr. DeFrances' lab is to elucidate the molecular mechanisms of PI3-kinase signal transduction, an key intracellular signaling pathway, in liver regeneration, metabolism and cancer using in vitro and in vivo models. Her lab has discovered a novel protein called PIK3IP1 (phosphatidylinositol-3-kinase interacting protein 1) which is a new type of PI3-kinase negative regulator. PIK3IP1 modulates PI3-kinase by virtue of a region of homology it shares with the p85 regulatory subunit of PI3-Kinase. PIK3IP1 binds to the catalytic p110 PI3-kinase subunit and downregulates its enzymatic activity in vitro and in vivo. Her lab examined PIK3IP1 expression in human liver tumors and noted its levels were reduced. In transgenic mice, overexpression of PIK3IP1 in hepatocytes suppressed HCC development and limited hepatocyte proliferation. Experiments are being carried out to determine the modalities that control PIK3IP1 function/activity. In addition, a conditional knock-out mouse model of PIK3IP1 is being created to further assess the role of PIK3IP1 in vivo.
Selected Publications:
View Dr. DeFrances' publications on PubMed
Ma, J., DeFrances, M.C., Zou, C., Johnson, C.J., Ferrell, R. and Zarnegar, R. (2009) "Somatic mutation and functional polymorphism of a novel regulatory element in the HGF gene promoter causes its aberrant expression in human breast cancer" Journal of Clinical Investigation (In Press; online publication: doi:10.1172/JCI36640)
He, X, Zhu, Z, Johnson, CJ, Stoops, J, Eaker, AE, Bowen, W and DeFrances, M.C. (2008) "PIK3IP1, a negative regulator of PI3K, suppresses hepatocarcinogenesis" Cancer Research 68: 5591-5598
Wu, T, Li, G, Lim, K, DeFrances, M.C., Chandrashekhar, G, and Han, C. (2008) "Transgenic expression of cyclooxygenase-2 in hepatocytes accelerates endotoxin-induced acute liver failure" The Journal of Immunology 181: 8027 - 8035
Zhu, Z, Hu, X, Johnson, CJ, Stoops, J, Eaker, AE, Bell, A, Stoffer, D, Zarnegar, R., and DeFrances, M.C. (2007) "PI3K is negatively regulated by PIK3IP1, a novel p110 interacting protein" Biochem. and Biophys. Res. Commun. 358: 66-72
Zou, C., Ma, J., Strom, S., Michalopoulos, G.K., DeFrances, M.C., and Zarnegar, R. (2007) "Lack of Fas antagonism by Met in fatty liver disease: The alpha chain of Met is a natural antagonist of FasL via a novel YLGA motif" Nature Medicine 13: 1078 - 1085
Yu, YP, Yu, G, Tseng, G, Cieply, K, Nelson, J, DeFrances, M.C., Zarnegar, R, Michalopoulos, GK, and Luo, JH (2007) "Glutathione Peroxidase 3, Deleted or Methylated In Prostate Cancer, Suppresses Prostate Cancer Growth and Metastasis" Cancer Research 67: 8043-50.
Michalopoulos GK, DeFrances M. Liver regeneration. Adv Biochem Eng Biotechnol. 2005;93:101-34. Review.
Wang, X. DeFrances, M.C., Dai, Y. Bell, A., Michalopoulos G.K. and R. Zarnegar (2002). A novel mechanism of cell survival: sequestration of the death receptor Fas by direct physical association with the tyrosine kinase receptor Met. Molecular Cell 9:411-422.
Recent Review Articles & Book Chapters:
DeFrances, M.C. "Molecular Mechanisms of Hepatocellular Carcinoma: Insights to Therapy" in Hepatocellular Carcinoma: Diagnosis and Treatment, 2nd Edition Ed. by B. Carr, Humana Press, Totowa, NJ (In Press)
Michalopoulos, G.K. and DeFrances, M.C. (2008) "Liver Regeneration," in The Textbook of Gastroenterology, 5th Edition Chapter 28, Ed. By T. Yamada et al., Lippincott Williams & Wilkins, Hagerstown, MD
DeFrances, M.C. and Michalopoulos, G.K. (2005) "Molecular Mechanisms of Hepatocellular Carcinoma: Insights to Therapy" in Hepatocellular Carcinoma: Diagnosis and Treatment, Ed. by B. Carr, Humana Press, Totowa, NJ, pp. 23-58.
Michalopoulos, G. and DeFrances, M.C. (2005) "Liver Regeneration" in "Regenerative Medicine," Ed. by I. Yannas, Advances in Biochemical Engineering/Biotechnology 93: 101-134.
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