Activation of HTLV-I gene transcription by protein tyrosine phosphatase inhibitors

• Published in: Virology (New York, N.Y.) Vol. 329; no. 2; pp. 395 - 411
• Main Authors: Langlois, Mélanie, Audet, Brigitte, Legault, Éric, Paré, Marie-Ève, Ouellet, Michel, Roy, Jocelyn, Dumais, Nancy, Mesnard, Jean-Michel, Rothstein, David M., Marriott, Susan J., Tremblay, Michel J., Barbeau, Benoit
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.11.2004; Elsevier
• Subjects: Cancer; Cell Line; Colforsin - pharmacology; CREB; Cyclic AMP Response Element-Binding Protein; Cyclic AMP Response Element-Binding Protein - physiology; Dinoprostone; Dinoprostone - pharmacology; Drug Synergism; Enzyme Inhibitors; Enzyme Inhibitors - pharmacology; Forskolin; Gene Expression Regulation, Viral; Gene Expression Regulation, Viral - drug effects; Gene Products, tax; Gene Products, tax - physiology; HTLV-I; Human T-lymphotropic virus 1; Human T-lymphotropic virus 1 - genetics; Human T-lymphotropic virus 1 - metabolism; Humans; Intracellular Signaling Peptides and Proteins; Life Sciences; LTR; Microbiology and Parasitology; Organometallic Compounds; Organometallic Compounds - pharmacology; Protein tyrosine phosphatase; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - metabolism; Protein Tyrosine Phosphatases - physiology; Protein-Tyrosine Kinases; Protein-Tyrosine Kinases - metabolism; SHP1 Protein Tyrosine Phosphatase; Terminal Repeat Sequences; Transcription, Genetic; Transcription, Genetic - drug effects; Vanadates; Vanadates - pharmacology; Virology; Virus Activation; ZAP-70 Protein-Tyrosine Kinase; HTLV-I; CREB; LTR; Protein tyrosine phosphatase
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2004.09.003

Human T-cell leukemia virus type I (HTLV-I) transcription generally depends on the ability of the viral Tax protein to bind the CREB transcription factor and form an active complex by recruiting CBP/p300 coactivators to the long terminal repeat (LTR). Studies have demonstrated that T-cell activating agents that stimulate CREB are potent inducers of HTLV-I transcription. Herein, we demonstrate that bpV[pic], a protein tyrosine phosphatase (PTP) inhibitor activates the HTLV-I LTR in the presence and absence of Tax expression. Optimal activation occurred at 8 h and was synergistic with forskolin or PGE 2. Infected cell lines and cells transfected with HTLV-I proviral DNA were equally responsive to the synergistic effect of bpV and forskolin on HTLV-I gene expression. Activation of the LTR by bpV[pic] was T-cell receptor-independent, but required ZAP70, calcineurin activity and functional calcium entry. Inhibition of the SHP-1 PTP was suggested to be important. Transfection experiments with a CREB dominant-negative mutant and with isolated TRE1- or CREB-responsive reporter constructs and treatment with the MDL-12,330A adenylate cyclase inhibitor all supported the involvement of a CREB/ATF family member in this bpV-dependent activation of the HTLV-I LTR, although CREB itself did not seem to be involved. Analysis of HTLV-I reporter constructs containing mutated CREB-binding sites also implied the involvement of another element in this activation. These results demonstrate for the first time a powerful effect of PTP inhibitors on HTLV-I LTR activity and suggest participation of both CREB-dependent and -independent pathways in this activation.