Activation of HTLV-I gene transcription by protein tyrosine phosphatase inhibitors.
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.
Langlois
Mélanie
M
Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, Ste-Foy (Québec), Canada G1V 4G2.
Audet
Brigitte
B
Legault
Eric
E
Paré
Marie-Eve
ME
Ouellet
Michel
M
Roy
Jocelyn
J
Dumais
Nancy
N
Mesnard
Jean-Michel
JM
Rothstein
David M
DM
Marriott
Susan J
SJ
Tremblay
Michel J
MJ
Barbeau
Benoit
B
D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D015232:Dinoprostone / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D016356:Gene Products, tax / Q000502:physiology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009942:Organometallic Compounds / Q000494:pharmacology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020079:Terminal Repeat Sequences; D014158:Transcription, Genetic / Q000187:drug effects*; D014638:Vanadates / Q000494:pharmacology*; D014775:Virus Activation; D051746:ZAP-70 Protein-Tyrosine Kinase
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D016356:Gene Products, tax; D047908:Intracellular Signaling Peptides and Proteins; D009942:Organometallic Compounds; C119540:oxodiperoxo(pyridine-2-carboxylate)vanadate(V); C069276:peroxovanadate; D005576:Colforsin; D014638:Vanadates; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D015232:Dinoprostone