Cyclin E and Bcl-xL cooperatively induce cell cycle progression in c-Rel-/- B cells.
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.
Cheng
Shuhua
S
Division of Immunology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Hsia
Constance Yu
CY
Leone
Gustavo
G
Liou
Hsiou-Chi
HC
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology*; D019927:Cyclin E / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D019927:Cyclin E; D019253:Proto-Oncogene Proteins c-bcl-2; D020569:Proto-Oncogene Proteins c-rel; D016160:Retinoblastoma Protein; D051020:bcl-X Protein; D018844:Cyclin-Dependent Kinases