Disease relevance of TLX2

• Transient transfections and electrophoretic-mobility-shift assays suggested that PHOX2B is able to bind the cell-specific element in the 5' regulatory region of the TLX2 gene, determining its transactivation in neuroblastoma cells [1].
• Finally, PHOX2B proteins carrying mutations responsible for CCHS (congenital central hypoventilation syndrome) development showed a severe impairment in activating TLX2 expression, both in vitro and in vivo [1].
• HOX11L1 is a homeobox gene involved in peripheral nervous system development as confirmed by knockout mice exhibiting megacolon with enteric ganglia, a phenotype associated in human with Intestinal Neuronal Dysplasia (IND) [2].
• HOX11L1 and HOX11 expression were observed in one instance each, in the absence of detectable chromosomal abnormality of their respective loci, on chromosomes 2 and 10, respectively [3].
• Our data suggest that NCX1 is a novel regulatory target for calcineurin and that depressed NCX activity might contribute to the etiology of in vivo cardiac hypertrophy and dysfunction occurring under conditions in which both calcineurin and protein kinase C are chronically activated [4].

Psychiatry related information on TLX2

• The dynamic regulation of the functional state of activated microglia by NCX 2216 helps explaining recent findings in Alzheimer's disease animal models and may offer new therapeutic opportunities for treating neurodegenerative diseases [5].
• CONCLUSION: Our results provide a rationale for future use of NCX 911 and S-nitrosothiols in the pharmacotherapy of erectile dysfunction (ED) [6].

High impact information on TLX2

• The plasma membrane Na+/Ca2+ exchanger (NCX) is almost certainly the major Ca2+ extrusion mechanism in cardiac myocytes [7].
• Specific point mutations in either domain largely allow the interchange of their functionality and uncover the mechanism underlying Ca2+ sensing in NCX [7].
• Effects of a nitroxybutylester derivative of aspirin (NCX 4215) on platelet aggregation and prostanoid synthesis were compared to the effects of aspirin [8].
• NCX 4215 did not alter systemic arterial blood pressure when administered intravenously to the rat [8].
• The sodium-calcium exchanger (NCX) is a critical mediator of calcium homeostasis [9].

Chemical compound and disease context of TLX2

• Inhibitory effect of NO-releasing ciprofloxacin (NCX 976) on Mycobacterium tuberculosis survival [10].
• Pertussis toxin normalised isoproterenol responses in NCX cells, indicating that beta2AR effects were mediated by Gi [11].
• The addition of 3',4'-dichlorobenzamil hydrochloride, an inhibitor of the Na+/Ca2+ exchanger (NCX), prevented the increase of eNOS activity with alkalosis [12].
• The amiloride derivative 2,4 dichlorobenzamil (DCB) inhibits the sodium-calcium exchanger (NCX) and was both antiproliferative and cytotoxic to glioma cells at low doses (20 microM) [13].
• Ouabain induces a form of hypertension mediated via the alpha2-Na+ pump isoform and the calcium influx mode of the vascular sodium calcium exchanger (NCX) [14].

Biological context of TLX2

• Such interaction was also confirmed in vivo by means of chromatin immunoprecipitation assay and, in addition, up-regulation of endogenous TLX2 mRNA level was demonstrated following PHOX2B over-expression, by quantitative real-time PCR [1].
• Taken together, these results support the PHOX2B-TLX2 promoter interaction, suggesting a physiological role in the transcription-factor cascade underlying the differentiation of neuronal lineages of the ANS during human embryogenesis [1].
• After characterizing a sequence displaying enhancer property in its 5' flanking region, we confirmed the functional link between the human PHOX2B and TLX2 genes [1].
• The TLX2 homeobox gene is a transcriptional target of PHOX2B in neural-crest-derived cells [1].
• Gel shift assays performed with oligonucleotides spanning this promoter sequence showed a change of the SP1 interaction with its binding sites, consequent to transfection with HOX11L1 [15].

Anatomical context of TLX2

• Expression of 14-3-3eta shifts the predominant localization of TLX-2 in COS cells from the cytoplasm to the nucleus [16].
• Here we show that HOX11L1 enhances the activity of the c-RET promoter in SK-N-MC cell line by stimulating a region between -166 bp and -35 bp [15].
• HOX11L1, a gene involved in peripheral nervous system development, maps to human chromosome 2p13.1-->p12 and mouse chromosome 6C3-D1 [2].
• Tlx-2 and 14-3-3eta are expressed in the developing peripheral nervous system with spatially and temporally overlapping patterns, and they are also coexpressed in PC12 cells [16].
• Depressed NCX activity was partially and independently reversed by the acute inhibition of calcineurin and protein kinase C activities with little effect on myocyte hypertrophic phenotypes [4].

Associations of TLX2 with chemical compounds

• NCX 4215 was approximately seven times more potent than aspirin as an inhibitor of thrombin-induced human platelet aggregation in vitro, but did not inhibit platelet thromboxane synthesis or gastric prostaglandin synthesis [8].
• In the present study, employing two unrelated Na+/Ca2+ exchange inhibitors, 3',4'-dichlorobenzamil (DCB) and bepridil, we investigated the role of NCX in platelet activation induced by various agonists in detail [17].
• Biochemical and ultrastructural analyses showed that NCX inhibitors, particularly DCB, made platelets "thrombasthenic". These findings suggest that the NCX is involved in the common steps of inside-out signaling through integrin IIbbeta3 [17].
• Studies in cell lines and animal models have shown that flurbiprofen racemate, its R-enantiomer and its nitric oxide (NO)-releasing derivatives, HCT 1026 and NCX 2216, are effective on AD amyloid pathology [18].
• In hypertrophic neonatal rat cardiomyocytes subjected to chronic phenylephrine treatment, we observed a marked depression of NCX activity measured as the rate of Na(+)(i)-dependent (45)Ca(2+) uptake or the rate of Na(+)(o)-dependent (45)Ca(2+) efflux [4].

Other interactions of TLX2

• DQX1 is located between AUP1 and HOX11L1 in a gene-dense region of human Chromosome (Chr) 2p13 and mouse Chr 6 [19].

Analytical, diagnostic and therapeutic context of TLX2

• Aspirin (10-120 mg/kg) caused extensive hemorrhagic erosion formation in the stomach of the rat within 3 h of oral administration, while NCX 4215 did not produce significant damage at doses of up to 300 mg/kg, nor when given daily for two weeks at 166 mg/kg [8].
• NCX mRNA levels were studied using RNase Protection Assay (RPA) and NCX protein levels were assessed by Western blot [20].
• In reverse transcription polymerase chain reaction (RT-PCR) analysis, EBER-1 mRNAwas expressed in 74% (23/31) of ICC, 83% (19/23) of CIN, 37% (13/35) of NCX [21].
• The NCX formed between dynorphin 1-7 and Mini Gastrin I is used as a model system for comparison to previous MALDI experiments (Woods, A. S.; Huestis, M. A. J. Am. Soc. Mass Spectrom. 2001, 12, 88-96) [22].
• Surface plasmon resonance assays in NF MPs allowed us to demonstrate direct interaction between the NCX and caveolin-3 and immobilized annexin A5 [23].

References