Human T-cell leukemia virus type I tax masks c-Myc function through a cAMP-dependent pathway.
Human T-cell leukemia virus type I Tax is a pleiotropic gene regulator that functions through CREB/ATF- and NF-kappaB-mediated pathways. In most contexts, Tax is a potent gene activator. Here, we describe an unexpected finding of Myc repression by Tax. In cells that overexpress human T-cell leukemia virus type I Tax, the detection of c-Myc protein in the nucleus by a monoclonal antibody was masked. Tax prevented immunological visualization of a Myc epitope contained within amino acids 45-104, resulting in interference with Myc function in transcription and in anchorage-independent cell growth. Tax did not affect steady-state protein levels since detection of c-Myc with other antibodies was unperturbed. Four observations suggest that this Tax-Myc interaction is mediated through CREB/ATF signal transduction. 1) Tax point mutants, selectively defective for activation of CREB/ATF but not NF-kappaB, failed to mask c-Myc; 2) masking of Myc was abolished when Tax-expressing cells were treated with protein kinase inhibitor H-9; 3) Tax-specific shielding of Myc is absent in cells (B1R) that are genetically defective for cAMP signaling; and 4) forskolin treatment of cells mimicked Tax in masking the Myc epitope. Considered collectively, these findings suggest a regulation of Myc function at the level of localized protein conformation.
Semmes
O J
OJ
Molecular Virology Section, Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892.
Barret
J F
JF
Dang
C V
CV
Jeang
K T
KT
D000818:Animals; D002455:Cell Division; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis / Q000378:metabolism; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D000939:Epitopes / Q000032:analysis; D004926:Escherichia coli; D016356:Gene Products, tax / Q000378:metabolism*; D016259:Genes, myc; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D016296:Mutagenesis; D010957:Plasmids; D011487:Protein Conformation; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D015183:Restriction Mapping; D017384:Sequence Deletion; D015398:Signal Transduction; D014162:Transfection
D017362:Cyclic AMP Response Element-Binding Protein; D000939:Epitopes; D016356:Gene Products, tax; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D000242:Cyclic AMP; D015500:Chloramphenicol O-Acetyltransferase