Relevance of CREB phosphorylation in the anti-apoptotic function of human T-lymphotropic virus type 1 tax protein in serum-deprived murine fibroblasts.
The human T-cell leukemia virus type 1 (HTLV-1) Tax transactivator is thought to play a primary role in the development of HTLV-1-mediated diseases. Using a murine fibroblast model, we previously showed that Tax reduces apoptosis induced by serum starvation by preventing cytochrome c release from the mitochondria. As Tax can enhance the transcriptional activity of nuclear factor NF-kB and cAMP-responsive element binding protein/activating transcription factor-1 (CREB/ATF-1), we investigated the relevance of these routes in the anti-apoptotic effects of Tax. Results showed that a Tax mutant retaining CREB/ATF-1 transactivating activity protects murine fibroblasts from serum-depletion-induced apoptosis, while two CREB/ATF-1-defective mutants did not. Treatment with forskolin, an activator of CREB, significantly attenuated cytochrome c release and Bax translocation in response of serum deprivation. In analogy to forskolin treatment, Tax expression results in sustained phosphorylation of CREB at Ser(133) during serum starvation. Considered together, these results underscore a primary role of CREB transcriptional activation in preventing apoptosis triggered by growth factor withdrawal, and suggest that Tax might in part function by affecting the phosphorylation state of CREB.
Oncology Section, Department of Oncology and Surgical Sciences, University of Padova, Italy.
Roberta
R
Trevisan
Laura
L
Daprai
Lidia
L
Acquasaliente
Vincenzo
V
Ciminale
Luigi
L
Chieco-Bianchi
Daniela
D
Saggioro
D051697:Activating Transcription Factor 1; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001798:Blood Proteins / Q000172:deficiency; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000378:metabolism*; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology*; D051028:bcl-2-Associated X Protein
D051697:Activating Transcription Factor 1; C497100:Atf1 protein, mouse; C494826:BAX protein, human; C494827:Bax protein, mouse; D001798:Blood Proteins; D016895:Culture Media, Serum-Free; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D005576:Colforsin; D045304:Cytochromes c