Abstract
A tetracycline-regulated system was used to characterize the effects of c-Rel on cell proliferation. The expression of c-Rel in HeLa cells led to growth arrest at the G1/S-phase transition, which correlated with its nuclear localization and the induction of endogenous IkappaB alpha expression. These changes were accompanied by a decrease in E2F DNA binding and the accumulation of the hypophosphorylated form of Rb. In vitro kinase assays showed a reduction in Cdk2 kinase activity that correlated with elevated levels of p21WAF1 Cdk inhibitor and p53 tumor suppressor protein. While the steady-state levels of WAF1 transcripts were increased, pulse-chase analysis revealed a sharp increase in p53 protein stability. Importantly, the deletion of the C-terminal transactivation domains of c-Rel abolished these effects. Together, these studies demonstrate that c-Rel can affect cell cycle control and suggest the involvement of the p21WAF1 and p53 cell cycle regulators.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / physiology
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CDC2-CDC28 Kinases*
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Carrier Proteins*
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Cell Compartmentation
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Cell Cycle / physiology*
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Cell Cycle Proteins*
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Cell Division / physiology
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Cell Nucleus / metabolism
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Chickens
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinases / metabolism
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Cyclins / metabolism
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DNA-Binding Proteins / biosynthesis
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E2F Transcription Factors
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G1 Phase / physiology
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Gene Expression Regulation / drug effects
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HeLa Cells
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Humans
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I-kappa B Proteins*
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NF-KappaB Inhibitor alpha
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-rel
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Recombinant Proteins / metabolism
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Retinoblastoma Protein / metabolism
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Retinoblastoma-Binding Protein 1
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S Phase / physiology
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Tetracycline / pharmacology
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Transcription Factor DP1
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Transcription Factors / metabolism
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Tumor Suppressor Protein p53 / metabolism
Substances
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CDKN1A protein, human
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Carrier Proteins
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA-Binding Proteins
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E2F Transcription Factors
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I-kappa B Proteins
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NFKBIA protein, human
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-rel
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Recombinant Proteins
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Retinoblastoma Protein
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Retinoblastoma-Binding Protein 1
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Transcription Factor DP1
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Transcription Factors
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Tumor Suppressor Protein p53
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NF-KappaB Inhibitor alpha
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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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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases
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Tetracycline