Journal
ONCOGENE
Volume 22, Issue 52, Pages 8472-8486Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1206917
Keywords
B cell; lymphoma; leukemia; Rel; cyclin E; Bcl-x(L)
Funding
- NCI NIH HHS [CA 90405, CA 68155] Funding Source: Medline
- PHS HHS [1 T32 A1 07621] Funding Source: Medline
Ask authors/readers for more resources
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 G(1) 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-x(L). Here, we use the bcl-x(L) 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-x(L) 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-x(L) 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available