Activation of Bcl-2 promoter-directed gene expression by the human immunodeficiency virus type-1 Tat protein

Human immunodeficiency virus type 1 (HIV-I) Tat transcriptionally activates expression from a number of viral and cellular promoters. Recent studies d emonstrate the ability of Tat to differentially modulate cellular responses to apoptotic signaling. The antiapoptotic effects of Tat appear to correla te with increased expression of Bcl-2, a cellular protein that enhances cel lular survival. Here, endogenous expression of HIV-I Tat in HeLa and Jurkat cells elevates levels of Bcl-2. Transient expression assays performed in H eLa cells demonstrate that Tat directly or indirectly enhances Bcl-2 promot er-directed gene expression by more than 10-fold. Analyses of Tat mutants d emonstrate that two noncontiguous regions in the N- and C-termini of Tat me diate maximal transactivation of the Bcl-2 promoter. The requirement for C- terminal sequences contrasts with transactivation of the HIV-1 long termina l repeat in which the N-terminal 57 amino acids are required but downstream residues are not Bcl-2 promoter analyses suggest that sequences required f or Tat responsiveness are located upstream of P1 and between the P1 and P2 promoter units. Results from these studies reveal effects of HIV-1 Tat on B cl-2 expression and provide a putative mechanism by which endogenously expr essed Tat affects cellular survival through the up-regulation of Bcl-2. (C) 1999 Academic Press.