摘要：

as transcriptional coactivators by bridging a very large number of DNA-bound transcription factors with basal transcription complex (24 -26). p300/CBP also binds to a number of proteins that are not transcription factors including viral oncogene products (27, 28), SRC1 (29), Cdk2 (30), and a protein contain- ing enzymatic activity as histone acetyltransferase, p300/CBP- associated factor (31). Recent studies show that p300/CBP also has enzyme activity as a histone acetyltransferase, linking chromatin remodeling with transcription (32). It has been sug- gested that the amount of p300/CBP in cells may be rate- limiting and that different transcription factors may compete for rate-limiting amounts of these coactivators and thus pro- vide mechanisms for cross-talk in the regulation of gene ex- pression (33, 34). Targeted gene disruption studies have con- firmed that p300 function is essential for normal embryonic cellular proliferation, morphogenesis, and development with double knockouts resulting in 100% embryonic lethality (35). Normal levels of CBP in these mice did not substitute for the p300 functions suggesting that the double knock-out phenotype may be either due to gene dosage effect or the loss of specific functions provided by p300. Likewise, haploinsufficiency of CBP gives rise to severe developmental abnormalities charac- teristic of the Rubinstein-Taybi syndrome, including mental retardation, craniofacial abnormalities, skeletal abnormalities, and increased cancer incidence (36). These studies suggest that both proteins are required for embryonic development.Stromelysin is an important member of a family of matrix metalloproteases (MMPs) which degrade extracellular matrix during a variety of normal and pathological processes. In this paper, we show that two important members of the Ets family, Ets-1 and Ets-2, recruit p300/CBP in the activation of the stromelysin promoter, and this recruiting involves multiple protein-protein interactions. Consistent with these multiple interactions, the N- and the C-terminal halves of p300/CBP independently can coactivate Ets-2 to stimulate the stromely- sin promoter. Other Ets family transcription factors do not cooperate with p300/CBP in the stimulation of the stromelysin promoter. We also show that mutation of the Ets-2 MAP kinase phosphorylation site, important for Ras-mediated regulation of Ets-2, does not affect its ability to bind to p300/CBP or its ability to cooperate with p300/CBP in the transcriptional activation.

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