Regulation of apoptotic and growth inhibitory activities of C/EBPalpha in different cell lines.
C/EBPalpha is expressed in many tissues and inhibits cell growth. In this paper, we have examined mechanisms which regulate activities of C/EBPalpha in cell lines derived from different tissues. We found that C/EBPalpha possesses strong pro-apoptotic activity in NIH3T3 cells, while this activity is not detected in 3T3-L1, Hep3B2 and HEK293 cells. Micro-array data show that C/EBPalpha activates many genes of apoptosis signaling in NIH3T3 cells. One of these genes, ARL6IP5, is a direct target of C/EBPalpha and is a key mediator of the apoptosis. Using C/EBPalpha mutants which do not cause cell death; we have found that C/EBPalpha does not arrest proliferation of NIH3T3 cells. The lack of growth arrest in NIH3T3 cells correlates with the inhibition of p16INK4 and with low levels of cyclin D3. The limited growth inhibitory activity of C/EBPalpha is also observed in Hep3B2 cells which express low levels of cyclin D3. Elevation of cyclin D3 restores growth inhibitory activity of C/EBPalpha in NIH3T3 and in Hep3B2 cells. These data show that apoptotic and growth inhibitory activities of C/EBPalpha are differentially regulated in different cells and that cooperation of cyclin D3 and C/EBPalpha is required for the inhibition of proliferation.
Wang
Guo-Li
GL
Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Shi
Xiurong
X
Salisbury
Elizabeth
E
Timchenko
Nikolai A
NA
D048868:Adaptor Proteins, Signal Transducing; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D056743:Cyclin D3; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C485929:Arl6ip1 protein, mouse; D022763:CCAAT-Enhancer-Binding Protein-alpha; C534696:CCND3 protein, human; D002352:Carrier Proteins; C534697:Ccnd3 protein, mouse; D056743:Cyclin D3; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D008565:Membrane Proteins; D050505:Mutant Proteins; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; D051357:Cyclin-Dependent Kinase 2