The SRC-family protein tyrosine kinase, Lck, is required for cell cycle progression in nontransformed T lymphocytes

K. Al-Ramadi, H. Zhang, A. L.M. Bothwell

Research output: Contribution to journalArticlepeer-review

Abstract

We have previously described the derivation of Lck-deficient transfectants of a nontransformed Th2 clone using an antisense RNA approach (al-Ramadi et al, J. Immunol. 157:4751, 1996). In one of the transfectants, designated D8, Lck protein expression was inhibited by ∼97%. As a consequence, TCR-mediated signaling was dramatically affected, as evidenced by >90% inhibition of cellular proliferation in response to various antigenic and mitogenic stimuli. Analysis of protein tyrosine phosphorylation following TCR triggering revealed strikingly qualitative differences in phosphorylation patterns between normal and Lck-deficient T cells. One of those differences was the presence, in D8 T cells only, of a ∼32 kD-protein which was constitutively tyrosine-phosphorylated. In the present study, we provide evidence that the aberrantly hyperphosphorylated protein is p34cdc2, a key regulator of cell cycle progression. Lck-deficient cells expressed high levels of cdc2 protein and its regulatory units, cyclins A and B. However, despite the increased protein level, and owing to its tyrosine phosphorylation, cdc2 enzymatic function was suppressed, as demonstrated directly in a kinase assay. D8 T cells were significanlty larger in size than the parental D10 cells and contained 4N DNA. These results demonstrate that a deficiency in Lck PTK leads to a block in cell cycle at the G2/M transition and results in cellular accumulation at the G2 phase of the cell cycle.

Original languageEnglish (US)
Pages (from-to)A937
JournalFASEB Journal
Volume12
Issue number5
StatePublished - Mar 20 1998
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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