Disease relevance of CITED2

• The transcription factor CITED2 binds p300/CBP at the CH1 domain and functions as a negative regulator of hypoxia signaling by competing with hypoxia-inducible factor 1alpha [1].
• We present for the first time functionally relevant mutations of CITED2 in patients with congenital heart defects (CHDs) [2].
• Induction of CITED2 expression in the rat hippocampus following transient global ischemia [3].
• In this study, we confirmed that both mRNA and protein levels of Cited2 are down-regulated in MDA-MB-231 breast cancer cells [4].

High impact information on CITED2

• The high-resolution solution structure of the CITED2 TAD-p300 CH1 complex shows that the CITED2 TAD, like the HIF-1alpha C-TAD, folds on a helical, Zn2+-containing CH1 scaffold [5].
• These findings reveal that CITED2 regulates HIF-1 by competing for a hot spot on the p300 CH1 domain [5].
• This is the first demonstration that TGF-beta-mediated down-regulation of Cited2 is post-transcriptional, through the Smad pathway, and requires the presence of its coding sequence [4].
• We examined the expression of recombinant Cited2 gene introduced into MDA-MB-231 cells by stable transfection, and we found that mRNA containing the Cited2 protein-coding region controlled by a heterologous promoter indeed responds to TGF-beta-mediated down-regulation [4].
• Through microarray analysis, Cited2 was found to be down-regulated by transforming growth factor beta1 (TGF-beta) in various cell lines [4].

Chemical compound and disease context of CITED2

• CITED2 is inducible by varying stimuli including lipopolysaccharide, hypoxia, and cytokines such as interleukin 9 and interferon gamma [6].

Biological context of CITED2

• In transient transfection reporter assays, CITED2 acted as a dose-dependent coactivator of PPARalpha-dependent transcriptional regulation in the presence of several exogenous ligands [7].
• CITED2 also increased PPARgamma-dependent regulation of reporter genes but had no effect on PPARbeta activity [7].
• To determine whether CITED2 affects endogenous gene expression, this protein was stably overexpressed (CITED2+) or repressed by small inhibitor RNA (CITED2-) in immortalized mouse hepatocytes [7].
• Relative to the control stably transfected or CITED2-cells, CITED2+ cells had an increased rate of cell proliferation [7].
• The CITED2 gene is composed of three exons and two introns [8].

Anatomical context of CITED2

• Using the immortalized human chondrocyte cell line, C-28/I2, we investigated whether CITED2 could be responsive to mechanical stimuli, and if so, whether CITED2 could mediate shear-driven regulation of matrix metalloproteinase (MMP) genes [6].
• 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) [9].
• These studies identify a hierarchical network of transcription factors, including Wilms' tumor-1, steroidogenic factor-1, dosage-sensitive sex reversal, adrenal hypoplasia congenita, X-linked-1, PBX1, and CITED2, that both give rise to the adrenal cortex and subsequently determine its subsequent function in steroidogenesis [10].
• The persistent hypoxia and abnormal vasculature in the myocardium of interventricular septum in E15.5 Cited2(-/-) hearts were rescued with decreased HIF-1alpha gene dosage [11].
• Moreover, immunoblot analysis using mutant animals with germline deficiencies indicated that MRG-1 is synthesized predominantly in oocytes [12].

Associations of CITED2 with chemical compounds

• Pharmacologic inhibition of translation with cycloheximide attenuated Cited2 down-regulation by TGF-beta [4].
• This may occur through a direct physical association of Cited2 with Smads 2 and 3, as supported by co-immunoprecipitation, mammalian two-hybrid and glutathione S-transferase-pull down assays [13].
• There were gene specific differences, the PS2 and TGFbeta3 genes were about equally sensitive to Zeranol, 17beta-oestradiol and DES whereas a down-regulation of MRG1/p35srj could be detected at fmol/l concentrations of Zeranol whereas 17beta-oestradiol was several orders of magnitude less potent [14].

Physical interactions of CITED2

• In mammalian two-hybrid experiments, full-length p300 and TFAP2A interacted only when CITED2 was co-transfected [15].

Regulatory relationships of CITED2

• The results showed that flow shear at 5 dyn/cm2 increased CITED2 mRNA and protein levels and down-regulated MMP-1 and MMP-13 mRNA and protein levels as well as enzyme activities [6].
• These data suggest a model in which the Lhx2 LIM domain activates transcription through interaction with MRG1 leading to recruitment of p300/CBP and the TATA-binding protein [16].

Other interactions of CITED2

• The CITED2 TAD binds a different, more extensive surface of CH1 than does the HIF-1alpha C-TAD [5].
• CITED2 is implicated in the modulating the activity of HIF-1 which is a major transcription factor involved in ischemia-related gene expression [3].

Analytical, diagnostic and therapeutic context of CITED2

• Microarray analysis and real time PCR showed that several genes are differentially affected by PPARalpha ligands in CITED2+ versus CITED2-cells [7].
• Fluorescence in situ hybridization, and identity to a known human sequence-tagged site (D6S2114), was used to map the CITED2 gene to chromosome 6q23.3 [8].
• Molecular cloning and chromosomal localization of the human CITED2 gene encoding p35srj/Mrg1 [8].

References