Nuclear receptors regulate gene expression by direct activation of target genes and inhibition of AP-1. Here we report that, unexpectedly, activation by nuclear receptors requires the actions of CREB-binding protein (CBP) and that inhibition of AP-1 activity is the apparent result of competition for limiting amounts of CBP/p300 in cells. Utilizing distinct domains, CBP directly interacts with the ligand-binding domain of multiple nuclear receptors and with the p160 nuclear receptor coactivators, which upon cloning have proven to be variants of the SRC-1 protein. Because CBP represents a common factor, required in addition to distinct coactivators for function of nuclear receptors, CREB, and AP-1, we suggest that CBP/p300 serves as an integrator of multiple signal transduction pathways within the nucleus.

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Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. Moreover, tumor growth and metastasis formation are signi®cantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy. Keywords: cancer therapy/HDAC inhibitor/histone deacetylase/leukemia/valproic acid IntroductionLocal remodeling of chromatin and dynamic changes in the nucleosomal packaging of DNA are key steps in the regulation of gene expression, consequently affecting proper cell function, differentiation and proliferation. One of the most important mechanisms in chromatin remodeling is the post-translational modi®cation of the N-terminal tails of histones by acetylation, which apparently contributes to a`histone code' determining the activity of target genes (Strahl and Allis, 2000). Acetylation of histones and possibly other substrates is mediated by enzymes with histone acetyltransferase (HAT) activity. Conversely, acetyl groups are removed by histone deacetylases (HDACs). Both HAT and HDAC activities are recruited to target genes in complexes with sequencespeci®c transcription factors and their cofactors, e.g. corepressors such as N-CoR and SMRT, and coactivators (Chen and Evans, 1995;Ho Èrlein et al., 1995;Xu et al., 1999). Nuclear receptors were the main examples of transcription factors recruiting HAT-and HDAC-associated cofactors depending on their status of activation by an appropriate ligand (Alland et al., 1997;Heinzel et al., 1997;Nagy et al., 1997;Glass and Rosenfeld, 2000). Other transcription factors such as Mad-1, BCL-6 and ETO have also been shown to assemble HDAC-dependent transcriptional repressor complexes (Laherty et al., 1997;Dhordain et al., 1998;Gelmetti et al., 1998;Lutterbach et al., 1998;Wang et al., 1998).Inappropriate repression of genes required for cell differentiation has been linked to several forms of cancer, particularly to acute leukemia. In acute promyelocytic leukemia (APL) patients, retinoic acid receptor (RAR) fusion proteins (e.g. PML±RAR or PLZF±RAR) resulting from chromosomal translocations can interact with components of the corepressor complex (Grignani et al., 1998;Guidez et al., 1998;He et al., 1998;Lin et al., 1998). The hypothesis that corepressor-mediated aberrant repression may be causal for pathogenesis in APL is supported by the ®nding that the differentiation block in cells transformed by PLZF±RAR is overc...