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- Title
Cyclin E and Bcl-x<sub>L</sub> cooperatively induce cell cycle progression in c-Rel<sup>-/-</sup> B cells.
- Authors
Cheng, Shuhua; Yu Hsia, Constance; Leone, Gustavo; Liou, Hsiou-Chi
- Abstract
Aberrant overexpression of the c-rel protooncogene is associated with lymphoid malignancy, while c-rel deletion produces severe lymphoproliferative defects and immunodeficiency. To investigate the mechanism of c-rel-induced proliferation and cell cycle progression in B lymphocytes, we have compared signaling events elicited through the BCR in c-rel-/- and wild-type B cells. BCR stimulation of c-rel-/- B cells fails to induce proper cyclin expression, resulting in G1?phase arrest, but it is unclear whether these defects are in fact secondary events of decreased B-cell survival, since c-rel deletion also affects the expression of antiapoptotic genes such as bcl-xL. Here, we use the bcl-xL transgene to correct the viability of c-rel-deficient B cells, and show that the inhibition of apoptosis does not necessarily confer hyperproliferation of B cells activated through the BCR. c-rel-/- B cells still fail to enter the S?phase despite improved survival by bcl-xL overexpression, suggesting that c-Rel-associated cell cycle progression is dependent on more than just enhanced cell viability. Overexpression of cyclin E protein, however, can cooperate with Bcl-xL to restore cell cycle progression to c-rel-/- B cells via induction of the cyclin-CDK/Rb-E2F pathway. Furthermore, we show that c-Rel can directly regulate transcription of the e2f3a promoter/enhancer, which is then likely to lead to transcriptional activation of the cyclin E promoter by E2F3a. Hence, these studies provide clear evidence that control of lymphocyte proliferation via c-Rel is linked to a cyclin-dependent process, and suggest that c-Rel not only activates antiapoptotic signaling but also the induction of cell cycle progression.Oncogene (2003) 22, 8472-8486. doi:10.1038/sj.onc.1206917
- Subjects
ONCOGENES; LYMPHOCYTES; LEUCOCYTES; B cells; CYCLINS; CYCLIN-dependent kinases
- Publication
Oncogene, 2003, Vol 22, Issue 52, p8472
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1206917