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 linea ges, and highly expressed in several leukemia types. The Human T-cell Leuke mia Virus Type I (HTLV-I) is the etiological agent of Adult T-cell Leukemia /Lymphoma (ATLL), A previous report suggested that Tax, the viral transacti vator, is able to suppress the transactivation potential of c-Myb protein b y competing for recruitment of CBP, We tested whether such a competition co uld affect transcription from the c-Myb promoter in Tax expressing T-cells, Using several c-Myb promoter reporter constructs carrying mutations in var ious 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 t o interact with the full-length CBP and p300 proteins in vitro, and their a bility 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 rep ress the c-Myb promoter, suggesting that competition for CBP/p300 binding w as not the mechanism underlying Tax's effect. This concept was further supp orted by the fact that the Tax mutant V89A transrepresses the c-Myb promote r efficiently in spite of an impaired binding to CBP and p300, Therefore, T ax-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, In terestingly, a decreased transcription from the endogenous c-Myb promoter w as observed in several HTLV-I transformed T-cell lines. Finally, the abilit y 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 cadmi um-inducible promoter.