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

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:
Animals, Apoptosis, CDC2-CDC28 Kinases, Carrier Proteins, Cell Division, Cells, Cultured, Contact Inhibition, Culture Media, Serum-Free, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases, DNA Replication, Dimerization, Enzyme Activation, Fibroblasts, G0 Phase, G1 Phase, Phosphorylation, Protein Conformation, Protein Multimerization, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-bcl-2, Rats, Recombinant Fusion Proteins, Structure-Activity Relationship, bcl-Associated Death Protein, bcl-X Protein
Oncogene
Date: Jul. 27, 2001
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