HTLV-I Tax transrepresses the human c-Myb promoter independently of its interaction with CBP or p300.
The c-Myb proto-oncogene is preferentially expressed in hematopoietic lineages, and highly expressed in several leukemia types. The Human T-cell Leukemia Virus Type I (HTLV-I) is the etiological agent of Adult T-cell Leukemia/Lymphoma (ATLL). A previous report suggested that Tax, the viral transactivator, is able to suppress the transactivation potential of c-Myb protein by competing for recruitment of CBP. We tested whether such a competition could affect transcription from the c-Myb promoter in Tax expressing T-cells. Using several c-Myb promoter reporter constructs carrying mutations in various regions, we demonstrate that Tax suppression of c-Myb transactivation results in transrepression of the c-Myb promoter through the Myb responsive elements in Jurkat T-cells. The ability of Tax mutants M22, M47 and V89A to interact with the full-length CBP and p300 proteins in vitro, and their ability to repress the c-Myb promoter, was then evaluated. Although both M47 and M22 bind to CBP and p300 to a similar extent, only M47 was able to repress the c-Myb promoter, suggesting that competition for CBP/p300 binding was not the mechanism underlying Tax's effect. This concept was further supported by the fact that the Tax mutant V89A transrepresses the c-Myb promoter efficiently in spite of an impaired binding to CBP and p300. Therefore, Tax-mediated repression of the c-Myb promoter appears to be independent from a direct competition between c-Myb and Tax for recruitment of CBP/p300. Interestingly, a decreased transcription from the endogenous c-Myb promoter was observed in several HTLV-I transformed T-cell lines. Finally, the ability of Tax to directly repress the endogenous c-Myb promoter was demonstrated in a Jurkat cell line stably transfected with a tax gene driven by a cadmium-inducible promoter.
Nicot
C
C
Basic Research Laboratory, National Cancer Institute, Bethesda, Maryland 20814, USA.
Mahieux
R
R
Opavsky
R
R
Cereseto
A
A
Wolff
L
L
Brady
J N
JN
Franchini
G
G
D050882:CREB-Binding Protein; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000737:chemistry*; D006801:Humans; D019169:Jurkat Cells / Q000473:pathology / Q000821:virology; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic
D017362:Cyclic AMP Response Element-Binding Protein; D016356:Gene Products, tax; C000715470:MAS1 protein, human; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb; D015534:Trans-Activators; D050882:CREB-Binding Protein; C494363:CREBBP protein, human