CBP/p300 are bimodal regulators of Wnt signaling

Abstract

Many Wnts influence cell behavior by a conserved signaling cascade that promotes the stabilization and nuclear accumulation of b-catenin (b-cat), which then associates with TCF family members to activate target genes. The histone acetyltransferase CREB binding protein (CBP) can bind to TCF and inhibit Wnt signaling in Drosophila. In contrast, studies in vertebrates indicate a positive role for CBP and the closely related protein p300 as b-cat binding transcriptional co-activators. We address this discrepancy by demonstrating that in addition to its negative role, CBP has an essential positive role in Wnt signaling in flies. CBP binds directly to the C-terminus of Armadillo (Arm, the fly b-cat) and is recruited to a Wnt-regulated enhancer (WRE) in a Wnt-and Arm-dependent manner. In a human colorectal cancer cell line, we show that CBP and p300 can inhibit Wnt signaling and demonstrate that human p300 can bind directly to TCF4 in vitro. Our results argue that CBP/p300 has an evolutionarily conserved role as a buffer regulating TCF-b-cat/Arm binding. Subsequent to this interaction, it also has an essential role in mediating the transactivation activity of b-cat/Arm.

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

“…Supporting the previous study that proposed a FOSL1-dependent mechanism [11] in response to JQ1, our study suggests that FOSL1 and LEF1 might regulate transcription of non-BRD2 target genes presumably through BRD3 or BRD4. This result is consistent with the previous report that LEF1 acts as a coactivator in the presence of EP300 [45] and induces lung adenocarcinoma metastasis [46], while FOSL1 controls gene expression program mediating metastasis [47]. Since FOSL1 and LEF1 expression levels were reduced by JQ1 treatment, downregulation of their downstream target genes, such as IL6, FOS, and JUN, may lead to reduction of metastasis.…”

Inhibition by Chondroitin Sulfate E Can Specify Functional Wnt/β-Catenin Signaling Thresholds in NIH3T3 Fibroblasts

“…The mechanism by which Wnt3a/␤-catenin signaling differentially regulates transcriptional programs and biological function remains to be elucidated. In the absence of Wnt3a signaling, LEF and TCF function as transcriptional repressors by recruiting co-repressors such as Groucho to the classic Wnt response element (WRE) (45)(46)(47). When Wnt3a signaling is initiated, stabilized ␤-catenin can translocate to the nucleus and displace Groucho from the TCF/LEF complex, which switches the activity of the complex from a repressor to a transcriptional activator (47).…”

The microRNA miR-8 is a conserved negative regulator of Wnt signaling

“…pAc-miR-8 was generated by cloning a 500-bp genomic fragment containing the miR-8 hairpin. pAcArm* expresses a stabilized form of Arm as described (35). VP16-Lef1 is a fusion protein of the activation domain of VP16 with Lef1 (36).…”