Human CREB-binding Protein/p300-interacting Transactivator with ED-rich Tail (CITED) 4, a New Member of the CITED Family, Functions as a Co-activator for Transcription Factor AP-2

Abstract

Members of the CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) family bind CREB-binding protein and p300 with high affinity and regulate gene transcription. Gene knockout studies indicate that CITED2 is required for neural crest and neural tube development and that it functions as a co-activator for transcription factor AP-2 (TFAP2). Here we describe human CITED4, a new member of this family, which is encoded by a single exon mapping to chromosome 1p34 -1p35. CITED4 and p300/CREB-binding protein are present in endogenous naturally occurring complexes, indicating that they interact physiologically. The interaction occurs between the cysteine-histidinerich domain 1 of p300 and the carboxyl terminus of CITED4. In keeping with this, CITED4 functions as a transactivator when artificially targeted to a promoter element. CITED4 physically interacts with all TFAP2 isoforms in vitro and strongly co-activates all TFAP2 isoforms in Hep3B cells. Co-activation of TFAP2 requires amino-terminal and carboxyl-terminal residues of CITED4. In HepG2 cells, CITED4 is significantly weaker than CITED2 for TFAP2C co-activation. These results suggest that CITED4 may function as a co-activator for TFAP2. They also suggest the existence of cell type-and TFAP2 isoform-specific co-activation by CITED2 and CITED4, which may result in differential modulation of TFAP2 function.

Cited2 modulates TGF-β-mediated upregulation of MMP9

“…In this study, we have provided evidence supporting that Cited2 interacts with Smad3 and functions as a Smad3 co-activator in TGF-b signaling. Cited2 is recruited to (Glenn and Maurer, 1999), TFAP2 (Braganca et al, 2002;Braganca et al, 2003), the nuclear receptor PPAR (Tien et al, 2004), and HIF-1a Freedman et al, 2003;Fox et al, 2004) through interaction with CBP/p300. The role for CBP/p300 as an essential co-activator in Smad driven gene expression has been well documented by observations that overexpression of E1A antagonizes the function of CBP/ p300, which leads to attenuation of Smad-driven transcription Nishihara et al, 1998;Pouponnot et al, 1998;Topper et al, 1998).…”

“…The Cited (CBP/p300-interacting transactivators with glutamic acid (E)/aspartic acid (D)-rich C-terminal domain) gene family consists of four nuclear proteins -Cited1 (formerly MSG1) (Shioda et al, 1996(Shioda et al, , 1997Dunwoodie et al, 1998), Cited2 (formerly MRG1/ p35srj) (Shioda et al, 1997;Dunwoodie et al, 1998;Sun et al, 1998;Bhattacharya et al, 1999;Leung et al, 1999), Cited3 (Andrews et al, 2000), and Cited4 (formerly MRG2) (Braganca et al, 2002). Members of this family function as transcriptional co-activators without classical DNA-binding domains.…”

“…Cited2 interacts with the LIM domain of Lhx2 to enhance Lhx2-dependent transcription of LH/FSH glycoprotein a-subunit genes (Glenn and Maurer, 1999). Cited2 and Cited4 interact with TFAP2, thereby activating TFAP2-mediated transcription (Braganca et al, 2002. Transcriptional responses by Cited2 can be enhanced through its association with nuclear receptors, such as peroxisome proliferator activated receptor (PPAR), to enhance transcription of target genes (Tien et al, 2004).…”

Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q

“…Differentially expressed genes allowing for the discrimination between gliomas with and without 1p/19q losses were revealed by significance analysis of microarrays (SAM) followed by prediction analysis for microarrays (PAM) (Tusher et al, 2001;Tibshirani et al, 2002;Tews et al, 2006). One of the genes with significantly lower expression in 1p/19q-deleted gliomas was the CREBbinding protein (CBP)/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 4 gene (CITED4) at 1p34.2 (OMIM 606815), which has been linked to cancer-relevant cellular processes (Braganca et al, 2002;Fox et al, 2004). Here, we report on a detailed molecular analysis of CITED4 aberrations in human gliomas and provide evidence for an association of CITED4 hypermethylation with longer survival of oligodendroglial tumour patients.…”

“…The CITED4 gene encodes a 184-amino-acid protein of 24.5 kDa that binds CBP and the tumour suppressor protein EP300 (E1A-binding protein, 300 kDa), functions as a co-activator of the transcription factor AP-2 (Braganca et al, 2002), blocks binding of hypoxiainducible factor 1 alpha (HIF1a) to EP300 and inhibits HIF1a transactivation as well as hypoxia-mediated reporter gene activation (Fox et al, 2004). Loss of nuclear expression or cytoplasmic translocation of Most polymorphisms consist in exchanges or deletions of single nucleotides.…”