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Yiling Lu, M.D.
My primary research interest is to understand at the molecular level the cell-signaling mechanisms that lead to tumor cell growth and T-lymphocyte activation, especially in the field of protein and lipid kinase signaling.

We have demonstrated that, in correlation with amplified gene copy number of the p110a catalytic subunit of PI-3K in ovarian cancer cell lines and tumors, PI-3K activity and p110a expression are markedly increased compared with those of normal ovarian epithelium in 9 of 10 ovarian cancer cell lines and 5 of 5 tumors tested. Treatment of the ovarian cancer cell lines with PI-3K inhibitor LY294002 significantly reduces cell proliferation, arrests cell-cycle progression, and induces programmed cell death. The data indicate that increased PI-3K activity associated with increased PIK3CA copy number plays a significant role in ovarian cancer and suggests that PI-3K inhibitors may be used for tumor therapy.

We found that cells with mutant MMAC1 have high levels of AKT phosphorylation that can be reduced by PI-3K inhibitors. Introduction of MMAC1 into cells with mutant MMAC1 results in a marked decrease in both basal and ligand-induced AKT phosphorylation as well as AKT kinase activity. Strikingly, expression of MMAC1 does not alter basal and ligand-induced ERK1 or ERK2 MAP kinase phosphorylation. Further, expression of MMAC1 increases the rate of apoptosis. The data suggest that MMAC1 may function as a specific inhibitor of the PI-3K pathway and may act as a tumor suppressor by altering apoptosis.

My current research also characterized the involvement of PI-3K in the LCK-induced upregulation of EMT activity. EMT activation is induced in Jurkat T cells by CD28 or CD3 crosslinking. However, only CD28- but not CD3-induced EMT activity is inhibited by LY294002. Further, ligation of CD28 on Jurkat cells causes EMT association with PI-3K that does not occur in LCK-defective J.CaM1 cells. This association requires tyrosine phosphorylation and is mediated by binding of the SH2 domain of EMT binding to tyrosine-phosphorylated PI-3K. CD28 is an obligatory receptor to provide costimulatory signals for T-cell activation, which exacerbates immunologic rejection of tumor cells. Understanding CD28 signaling will improve strategies of tumor therapy as well as selection of immune suppressors in the treatment of transplant rejection and autoimmune diseases.

Selected Publications:
  1. Gibson S, Truitt K, Lu Y, LaPushin R, Khan H, Imboden J, Mills GB. Efficient CD28 signaling leads to increases in the kinase activities of TEC family tyrosine kinase EMT/ITK and SRC family tyrosine kinase LCK. Biochem J 330:1123-1128, 1998
  2. Lu Y, Cuevas B, Gibson S, Khan H, LaPushin R, Imboden J, Mills GB. Phosphatidylinositol 3-kinase is required for CD28 but not CD3 regulation of the Tec family tyrosine kinase EMT/ITK/TSK: functional and physical interaction of EMT with phosphatidylinositol 3-kinase. J Immunol 161:5404-5412, 1998
  3. Lu Y, Rodriguez RR, Bjorndahl JM, Phillips CA, Trevillyan JM. CD28-dependent killing by human YT cells requires phosphatidylinositol 3-kinase activation. Eur J Immunol 26:1278-1284, 1996
  4. Xu Y, Fang X, Furui T, Sasagawa T, Pustilnik T, Lu Y, Shen Z, Weiner JR, Shayesteh L, Gray JW, Bast RC Jr, Mills GB. Regulation of growth of ovarian cancer cells by phospholipid growth factors. In: Mason P, Sharp F, Blackett T, Bast RC (eds). Ovarian Cancer VI, pp 109-120. London: Chapman & Hall Medical, 1998