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.
- 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,
- 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
- 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
- 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