Activation of Gadd34 by diverse apoptotic signals and suppression of its growth inhibitory effects by apoptotic inhibitors.
DNA damage has many cellular consequences including, in some cases, apoptosis. Expression of Gadd34 was shown to be increased by ionizing radiation only in cells that undergo rapid apoptosis following this treatment. The effects of various other apoptosis-inducing agents as well as apoptosis-inhibiting genes on regulation of Gadd34 were investigated. In many cell types, agents which have been reported to lead to increased intracellular ceramide levels led to an increase in Gadd34 transcript levels. These included TNFalpha, the ceramide analog C-2 ceramide, dimethyl sphingosine and anti-Fas antibody as well as ionizing radiation. Induction of Gadd34 by ionizing radiation was coincident with the onset of apoptosis and increased as apoptosis progressed. In a short-term transfection assay, more than 30% of Gadd34-transfected cells exhibited nuclear fragmentation by 48 hours. Apoptosis, as well as induction of Gadd34 by apoptotic stimuli, was attenuated by the apoptosis inhibitors, Bcl-2, cowpox virus CrmA and herpes simplex virus ICP34.5. Thus, activation of Gadd34 is a downstream event in apoptotic signaling pathways and may directly contribute to the apoptotic process.
Basic Research Laboratory, Division of Basic Science, National Cancer Institute, Bethesda, Maryland 20892, USA. ch96b@nih.gov
M C
MC
Hollander
M S
MS
Sheikh
K
K
Yu
Q
Q
Zhan
M
M
Iglesias
C
C
Woodworth
A J
AJ
Fornace
D000943:Antigens, Differentiation; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D054645:Protein Phosphatase 1; D011506:Proteins / Q000378:metabolism* / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000494:pharmacology; D011839:Radiation, Ionizing; D015843:Serpins / Q000494:pharmacology; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells; D015854:Up-Regulation; D014764:Viral Proteins / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D022762:CCAAT-Enhancer-Binding Proteins; D018797:Cell Cycle Proteins; D002518:Ceramides; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D054645:Protein Phosphatase 1; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D015843:Serpins; D013110:Sphingosine; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D019014:fas Receptor; D000097642:GADD45 Proteins; C493956:CDKN1A protein, human; C497249:DDIT3 protein, human; C064769:N-acetylsphingosine; C066469:gamma 34.5 protein, Human herpesvirus 1; C007293:DAPI; C074641:interleukin-1beta-converting enzyme inhibitor; C087519:PPP1R15A protein, human; C061800:N,N-dimethylsphingosine