Factor-specific modulation of CREB-binding protein acetyltransferase activity (p300/CBP interacting proteinyp300/CBP associated factoryE1A)

CREB-binding proteins (CBP) and p300 are essential transcriptional coactivators for a large number of regulated DNA-binding transcription factors, including CREB, nuclear receptors, and STATs. CBP and p300 function in part by mediating the assembly of multiprotein complexes that contain additional cofactors such as p300yCBP interact- ing protein (pyCIP), a member of the p160ySRC family of coactivators, and the p300yCBP associated factor pyCAF. In addition to serving as molecular scaffolds, CBP and p300 each possess intrinsic acetyltransferase activities that are required for their function as coactivators. Here we report that the adenovirus E1A protein inhibits the acetyltransferase activity of CBP on binding to the CyH3 domain, whereas binding of CREB, or a CREByE1A fusion protein to the KIX domain, fails to inhibit CBP acetyltransferase activity. Surprisingly, pyCIP can either inhibit or stimulate CBP acetyltransferase activity depending on the specific substrate evaluated and the functional domains present in the pyCIP protein. While the CBP interaction domain of pyCIP inhibits acetylation of histones H3, H4, or high mobility group by CBP, it enhances acetylation of other substrates, such as Pit-1. These observa- tions suggest that the acetyltransferase activities of CBPyp300 and pyCAF can be differentially modulated by factors binding to distinct regions of CBPyp300. Because these interactions are likely to result in differential effects on the coactivator functions of CBPyp300 for different classes of transcription factors, regulation of CBPyp300 acetyltransferase activity may represent a mechanism for integration of diverse signal- ing pathways.