BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest.

Chattopadhyay A, Chiang CW, Yang E
Oncogene. 2001 20 (33): 4507-18

PMID: 11494146 · DOI:10.1038/sj.onc.1204584

The pro-apoptotic molecule BAD binds BCL-[X(L)] or BCL2 and inactivates their survival function. In addition to their anti-apoptotic function, BCL2 and BCL-[X(L)] 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-[X(L)] 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-x(L) heterodimers, rather than the absence of BCL-[X(L)] or BAD. These data provide evidence that in addition to regulating apoptosis, the BAD/BCL-[X(L)] heterodimer has a novel cell cycle function.

MeSH Terms (27)

Animals Apoptosis bcl-Associated Death Protein bcl-X Protein Carrier Proteins CDC2-CDC28 Kinases Cell Division Cells, Cultured Contact Inhibition Culture Media, Serum-Free Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases Dimerization DNA Replication Enzyme Activation Fibroblasts G1 Phase Phosphorylation Protein-Serine-Threonine Kinases Protein Conformation Protein Multimerization Protein Processing, Post-Translational Proto-Oncogene Proteins c-bcl-2 Rats Recombinant Fusion Proteins Resting Phase, Cell Cycle Structure-Activity Relationship

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