INTERPLAY OF STEROID-HORMONE RECEPTORS AND TRANSCRIPTION FACTORS ON THE MOUSE MAMMARY-TUMOR VIRUS PROMOTER

The mouse mammary tumor virus (MMTV) promoter, that responds to glucocorticoids and progestins, contains a complex hormone response element (HRE) in the long terminal repeat (LTR) region covered by a phased nucleosome. Hormone treatment leads to alterations in chromatin structure that make the HRE region more accessible to digestion by DNase I and permit binding of transcription factors. including nuclear factor I (NFI), immediately downstream of the HRE. NFI acts as a basal transcription factor on the MMTV promoter in vitro but competes with the hormone receptors in terms of binding to free DNA. In uninduced chromatin, the precise positioning of the DNA double helix on the surface of the histone octamer precludes binding of NFI to its cognate sequence while still allowing recognition of the HRE by the hormone receptors. We postulate that receptor binding to the nucleosomally organized MMTV promoter disrupts the chromatin structure enabling NFI binding and subsequent formation of a stable transcription complex. Whether the receptor remains bound to DNA during induction or is displaced by NFI is not conclusively known, but our evidence supports a "hit and run" mechanism. NFI is not the only factor involved in hormonally induced transcription of the MMTV promoter. Two degenerated octamer motifs located immediately upstream of the TATA box are recognized by the ubiquitous transcription factor OTF-1 (Oct-1, NFIII), and are also important. In vitro, mutations in these motifs do not influence basal transcription, but completely abolish the stimulatory effect of purified progesterone receptor. Progesterone receptor bound to the HRE facilitates binding of OTF-1 to the two octamer motifs. Thus, OTF-1 is a natural mediator of progesterone induction of the MMTV promoter and acts through cooperation with the hormone receptor for binding to DNA.