Evidence for cyclin D3 as a novel target of rapamycin in human T lymphocytes.
The immunosuppressant rapamycin has been shown to inhibit G(1)/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 p27(Kip1) (p27) and inhibition of p70 s6 kinase (p70(s6k)). However, recent evidence suggests that cells still remain sensitive to rapamycin in the absence of functional p27 or p70(s6k). 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.
Hleb
Marija
M
Department of Pediatrics, Brown Medical School, Women and Infant's Hospital of Rhode Island, Providence, Rhode Island 02905, USA.
Murphy
Shaun
S
Wagner
Eric F
EF
Hanna
Nazeeh N
NN
Sharma
Nishant
N
Park
Jungchen
J
Li
Xian C
XC
Strom
Terry B
TB
Padbury
James F
JF
Tseng
Yi-Tang
YT
Sharma
Surendra
S
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D056743:Cyclin D3; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000737:chemistry / Q000378:metabolism; D016213:Cyclins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D046911:Macromolecular Substances; D011518:Proto-Oncogene Proteins; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; C534696:CCND3 protein, human; D056743:Cyclin D3; D016213:Cyclins; D046911:Macromolecular Substances; D011518:Proto-Oncogene Proteins; D015759:Ionomycin; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D013755:Tetradecanoylphorbol Acetate; D020123:Sirolimus