Abstract
The anti-apoptotic molecules BCL-x(L) and BCL2 delay cell cycle entry from quiescence. We used serum induction and induction of a Myc-estrogen receptor fusion protein (MycER) in quiescent fibroblasts to investigate the mechanisms underlying the cell cycle activity of BCL-x(L) and BCL2. We demonstrate for the first time that BCL-xL and BCL2 delayed serum-induced and Myc-induced, but not E2F-induced, cell cycle entry. The cyclin-dependent kinase inhibitor p27 was elevated during serum deprivation and cell cycle entry in BCL-x(L) or BCL2-expressing NIH3T3 cells and a Rat1MycER cell line. Activation of cyclin-dependent kinase 2 (cdk2) and cyclin-dependent kinase 4 (cdk4) were delayed during progression to S phase, while the induction of cyclin D1 protein, as well as the levels of cyclin E, cdk2, and cdk4 were unaltered by BCL-x(L) or BCL2. Inhibition of cyclin/cdk activities in BCL-x(L) or BCL2 expressing cells was associated with excess p27 in the cyclin/cdk complexes. Neither BCL-x(L) nor BCL2 delayed S phase entry in cells deficient in p27, thus p27 is required for the cell cycle function of BCL-x(L) and BCL2. The cell cycle effects of BCL-x(L) and BCL2 were more profound in Myc-induced than in serum-induced cell cycle entry. Our results suggest that one possible mechanism by which BCL-x(L) and BCL2 delay cell cycle entry may be the inhibition of Myc activity through the elevation of p27.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Animals
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CDC2-CDC28 Kinases*
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Cattle
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Cell Cycle / physiology*
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology*
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Culture Media / pharmacology
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Culture Media, Serum-Free / pharmacology
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Cyclin D1 / physiology
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Cyclin D2
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Cyclin D3
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Cyclin E / physiology
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / physiology
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Cyclins / physiology
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DNA-Binding Proteins*
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E2F Transcription Factors
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Fetal Blood / physiology
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G1 Phase
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Gene Expression Regulation / drug effects
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Genes, bcl-2
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Genes, myc
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Humans
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Mice
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Protein Serine-Threonine Kinases / physiology
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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Proto-Oncogene Proteins c-myc / physiology*
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Proto-Oncogene Proteins*
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Rats
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Receptors, Estrogen / genetics
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Recombinant Fusion Proteins / physiology
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S Phase
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Tetracycline / pharmacology
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Transcription Factors / physiology
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology*
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bcl-X Protein
Substances
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BCL2L1 protein, human
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Bcl2l1 protein, mouse
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Bcl2l1 protein, rat
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CCND2 protein, human
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CCND3 protein, human
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Ccnd2 protein, mouse
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Ccnd2 protein, rat
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Ccnd3 protein, mouse
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Ccnd3 protein, rat
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Cdkn1b protein, mouse
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Cdkn1b protein, rat
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Cell Cycle Proteins
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Culture Media
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Culture Media, Serum-Free
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Cyclin D2
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Cyclin D3
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Cyclin E
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Cyclins
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DNA-Binding Proteins
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E2F Transcription Factors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-myc
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Receptors, Estrogen
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Recombinant Fusion Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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bcl-X Protein
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Cyclin D1
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Cyclin-Dependent Kinase Inhibitor p27
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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CDK2 protein, human
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CDK4 protein, human
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Cdk2 protein, mouse
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Cdk2 protein, rat
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Cdk4 protein, mouse
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Cdk4 protein, rat
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases
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Tetracycline