CELL-CYCLE ARREST AND APOPTOSIS HYPERSUSCEPTIBILITY AS A CONSEQUENCE OF LCK DEFICIENCY IN NONTRANSFORMED T-LYMPHOCYTES

Citation
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
Citations number
38
Categorie Soggetti
Multidisciplinary Sciences
ISSN journal
00278424
Volume
95
Issue
21
Year of publication
1998
Pages
12498 - 12503
Database
ISI
SICI code
0027-8424(1998)95:21<12498:CAAAHA>2.0.ZU;2-O
Abstract
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.