Bk. Alramadi et al., CELL-CYCLE ARREST AND APOPTOSIS HYPERSUSCEPTIBILITY AS A CONSEQUENCE OF LCK DEFICIENCY IN NONTRANSFORMED T-LYMPHOCYTES, Proceedings of the National Academy of Sciences of the United Statesof America, 95(21), 1998, pp. 12498-12503
By using antisense RNA, Lck-deficient transfectants of a T helper 2 (T
h2) clone have been derived and shown to have a qualitative defect in
the T cell receptor signaling pathway. A striking feature observed onl
y in Lck-deficient T cells was the presence of a constitutively tyrosi
ne-phosphorylated 32-kDa protein. In the present study, we provide evi
dence that this aberrantly hyperphosphorylated protein is p34(cdc2) (c
dc2) a key regulator of cell-cycle progression. Lck-deficient transfec
tants expressed high levels of cdc2 protein and its regulatory units,
cyclins A and B. The majority of cdc2, however, was tyrosine-phosphory
lated and therefore enzymatically inactive. The transfectants were sig
nificantly larger than the parental cells and contained 4N DNA, These
results establish that a deficiency in Lck leads to a cell-cycle arres
t in G(2), Moreover, transfected cells were hypersusceptible to apopto
sis when activated through the T cell receptor. Importantly, however,
this hypersusceptibility was largely reversed in the presence of T cel
l growth factors. These findings provide evidence that, in mature T ly
mphocytes, cell-cycle progression through the G(2)-M check point requi
res expression of the Src-family protein tyrosine kinase, Lck, This re
quirement is Lck-specific; it is observed under conditions in which th
e closely related Fyn kinase is expressed normally, evincing against a
redundancy of function between these two kinases.