CHOP (GADD153) is a protein of the C/EBP family of transcriptional regulators, which dimerizes with other C/EBP members and changes their DNA-binding and transactivation properties. It induces growth arrest and apoptosis after endoplasmatic reticulum stress or DNA damage. CHOP is also expressed during early embryogenesis and upregulated in tumour tissues with defective Wnt signals. We report here that CHOP functions as a specific inhibitor of Wnt/T-cell factor (TCF) signalling. CHOP inhibits TCF-dependent transcription in human embryonic and colon cancer cell lines. Injection of CHOP mRNA into early Xenopus laevis embryos suppresses dorsal organizer formation and inhibits secondary axis formation and TCF-dependent transcription in response to Wnt-8, Dishevelled, b-Catenin and TCF-VP16. In embryos and human cells, this inhibition depends on the N-terminal transactivation domain of CHOP, whereas the C-terminal dimerization domain is dispensable. CHOP binds to TCF factors, thereby preventing the binding of TCF to its DNA recognition site. Our findings demonstrate a novel function of CHOP as a Wnt repressor.
The carboxyl-terminal domain (CTD) of the large subunit of mammalian RNA polymerase II contains 52 repeats of a heptapeptide that is the target of a variety of kinases. The hyperphosphorylated CTD recruits important factors for mRNA capping, splicing, and 3-processing. The role of the CTD for the transcription process in vivo, however, is not yet clear. We have conditionally expressed an ␣-amanitin-resistant large subunit with an almost entirely deleted CTD (LS*⌬5) in B-cells. These cells have a defect in global transcription of cellular genes in the presence of ␣-amanitin. Moreover, pol II harboring LS*⌬5 failed to transcribe up to the promoterproximal pause sites in the hsp70A and c-fos gene promoters. The results indicate that the CTD is already required for steps that occur before promoter-proximal pausing and maturation of mRNA.Eukaryotic mRNA synthesis is catalyzed by the multisubunit RNA polymerase II (pol II).1 The large subunit of pol II (LS) is highly conserved among eukaryotic RNA polymerases and also shows striking homology to the large subunit of Escherichia coli RNA polymerase (1). The LS has evolved a particularly structured carboxyl-terminal domain (CTD) that is not present in other RNA polymerases (2). This CTD comprises multiple copies of a heptapeptide repeat with the consensus sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser. The number of repeats varies from 26/27 in yeast to 52 in mouse and human cells (3). Deletion of more than half of the repeats in yeast and mouse interferes with cell viability (4 -6). Mice homozygous for a deletion of 13 repeats are smaller than wild-type littermates and have a high rate of neonatal lethality (7), suggesting that CTD is important in regulating growth during mammalian development. In cells, two forms of pol II are detectable containing either a hypophosphorylated (pol IIA) or hyperphosphorylated CTD (pol II0). Although pol IIA is consistently found in the initiation complex, pol II0 is associated with elongating complexes.An increasing number of genes have been shown to be regulated by promoter-proximal pausing of pol II. These genes include Drosophila hsp70 and hsp26 genes, as well as the mammalian c-myc, c-fos, and immunoglobulin genes (8 -15). The passage of the paused pol II into a processive mode coincides in vivo with hyperphosphorylation of the CTD (11, 16).Recent studies suggest that the hyperphosphorylated CTD functions as a platform for the assembly of complexes that cap, splice, cleave, and polyadenylate pre-mRNA (2, 17, 18). Capping of mRNA occurs shortly after transcription initiation (19), preceding other mRNA processing events such as mRNA splicing and polyadenylation. The capping enzyme is not stably associated with basal transcription factors or the RNA pol II holoenzyme but is directly and specifically recruited to the hyperphosphorylated form of CTD (20 -22, 24). Similarly, several components of the splicing machinery (25, 26) and related factors such as SR proteins and SR-like proteins (27-29) are recruited to pol II by the hyperphosphorylated CT...
Our results strongly suggest that SOCS-3 is one of the proteins which influence the ability of TRAIL and resveratrol to cause programmed cell death in prostate cancer.
TGF- induces apoptosis and inhibits the proliferation of EBV-negative B-lymphoma cell lines. In contrast, EBV-immortalized B cells are resistant to both the proapoptotic and the antiproliferative activities of TGF-. We have generated a lymphoblastoid cell line, in which we can switch on and off the EBV-specific transcriptional program driven by EBNA2. When these cells express the EBNA2-driven phenotype, they are resistant to TGF--mediated growth arrest. We used this cell line to readdress the question of how EBV can overcome the antiproliferative TGF- activity. We show here that EBVdriven cells remain TGF--responsive since TGF- target genes are readily induced. Thus, EBV can overcome TGF--mediated growth arrest without interfering with the core machinery of the TGF- signaling pathway, which links ligand binding to the induction of TGF- target genes.
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