Faculty Collaboration Database

Cyclin E and Bcl-xL cooperatively induce cell cycle progression in c-Rel-/- B cells. Oncogene 2003 Nov 20;22(52):8472-86

Date

11/25/2003

Pubmed ID

14627988

DOI

10.1038/sj.onc.1206917

Scopus ID

2-s2.0-0347383874 (requires institutional sign-in at Scopus site)   47 Citations

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.

Author List

Cheng S, Hsia CY, Leone G, Liou HC

Author

Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
B-Lymphocytes
Base Sequence
Cell Cycle
Cyclin E
Cyclin-Dependent Kinases
Mice
Molecular Sequence Data
Promoter Regions, Genetic
Proto-Oncogene Proteins c-bcl-2
Proto-Oncogene Proteins c-rel
Retinoblastoma Protein
bcl-X Protein