Evidence for cyclin D3 as a novel target of rapamycin in human T lymphocytes

Marija Hleb, Shaun Murphy, Eric F. Wagner, Nazeeh N. Hanna, Nishant Sharma, Jungchen Park, Xian C. Li, Terry B. Strom, James F. Padbury, Yi Tang Tseng, Surendra Sharma

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

The immunosuppressant rapamycin has been shown to inhibit G1/S transition of the cell cycle. This inhibition is thought to be mediated by maintenance of the threshold levels of cyclin-dependent kinase (CDK) inhibitor p27Kipl (p27) and inhibition of p76 s6 kinase (p70s6k). However, recent evidence suggests that cells still remain sensitive to rapamycin in the absence of functional p27 of p70s6k. Here, we show that rapamycin represses cyclin D3 levels in activated human T lymphocytes with no inhibitory effects on cyclin D2. Furthermore, rapamycin elicits similar cyclin D3 modulatory effects in B lymphocytes. The overall effect of rapamycin on cyclin D3 leads to impaired formation of active complexes with Cdk4 or Cdk6 and subsequent inhibition of cyclin D3/ CDK kinase activity. Decrease in cyclin D3 protein levels is due to translational repression and not due to attenuated transcription of the cyclin D3 gene. Importantly, stable overexpression of cyclin D3 (2-2.5 fold) in Jurkat T cell transfectants renders them resistant to lower doses (1-10 ng/ml) of rapamycin. These results point to a critical role of cyclin D3 in rapamycin-mediated immunosuppressive effects in T cells and cell cycle regulation in lymphocytes in general.

Original languageEnglish (US)
Pages (from-to)31948-31955
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number30
DOIs
StatePublished - Jul 23 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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