Abstract
The pro-apoptotic molecule BAD binds BCL-xL or BCL2 and inactivates their survival function. In addition to their anti-apoptotic function, BCL2 and BCL-xL also delay cell cycle entry from quiescence. We found that the BH3-only molecule BAD also exerted a cell cycle effect. BAD expression resulted in failure to cell cycle block in growth arrest conditions. In low serum and in confluence, fibroblasts constitutively or inducibly expressing BAD persisted in S phase, continued to incorporate BrdU, and exhibited sustained cyclin E/cdk2 activity. Mutation analysis indicated that the cell cycle effect of BAD was not dependent on its phosphorylation status or subcellular localization, but strictly co-segregated with BCL-xL binding. bclx−/− MEFs expressing BAD and bad−/− MEFs both arrested in G0/G1 in low serum similar to wild-type controls, suggesting that the ability to overcome the G0/G1 checkpoint resulted from the presence of BAD/BCL-xL heterodimers, rather than the absence of BCL-xL or BAD. These data provide evidence that in addition to regulating apoptosis, the BAD/BCL-xL heterodimer has a novel cell cycle function.
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Acknowledgements
We are grateful to Dr Stanley Korsmeyer for providing bad−/− mice and 10929 anti-BAD antibody, to Dr Kevin Roth for providing bclx+/− mice, and to Dr Lawrence Boise for anti-BCL-x antibodies. We thank Courtney Greider for assistance with kinase assays and Dr Jeffrey Rottman for expert computer assistance. We thank Drs Stephen Brandt, Scott Hiebert, and Mark Koury for helpful discussions and critical reading of the manuscript. Experiments were performed in part through use of the Vanderbilt University Medical Center Cell Imaging Resource supported by CA68485 and DK20593. This work was supported by NIH 1RO1CA78443 grant, and grants from Pfizer, Inc. and the V Foundation.
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Chattopadhyay, A., Chiang, CW. & Yang, E. BAD/BCL-xL heterodimerization leads to bypass of G0/G1 arrest. Oncogene 20, 4507–4518 (2001). https://doi.org/10.1038/sj.onc.1204584
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DOI: https://doi.org/10.1038/sj.onc.1204584
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