Disease relevance of MSX2

• Parietal foramina with cleidocranial dysplasia is caused by mutation in MSX2 [1].
• This novel apoptosis-regulating function of MSX2 may provide a new therapeutic target for pancreatic cancer [2].
• And interestingly, MSX2 also interacts with and inhibits the transactivation function of the related Tax1 protein encoded by the Human T-cell leukemia virus type 1 (HTLV-1) [3].
• However, the absence of MSX2 mutations in some of the FPP patients analysed and the presence of FPP associated with chromosome 11p deletions in DEFECT 11 (OMIM 601224) patients or associated with Saethre-Chotzen syndrome suggests genetic heterogeneity for this disorder [4].
• Known causes of coronal synostosis include haploinsufficiency of TWIST1 and a gain of function mutation in MSX2 [5].
• When MSX2 was inactivated in pancreatic cancer cells following transfection with an MSX2-specific small interfering RNA, Twist 1 was down-regulated [6].

Psychiatry related information on MSX2

• The planar rigidized molecule fluorazene (FPP) undergoes fast reversible intramolecular charge transfer (ICT) in the excited state, with a reaction time of 12 ps in the polar solvent ethyl cyanide at -45 degrees C. The ICT state of FPP has a dipole moment mu(e)(ICT) of 13 D, much larger than that of the locally excited state LE (1 D) [7].
• Recognised clinical signs include EXT, FPP, mental retardation, facial asymmetry, asymmetric calcification of coronary sutures, defective vision (severe myopia, nystagmus, strabismus), skeletal anomalies (small hands and feet, tapering fingers), heart defect, and anal stenosis [8].
• The study variables were PFM exercise adherence, pelvic muscle strength, Continence self-efficacy, geriatric depression and incontinence stress [9].

High impact information on MSX2

• We previously identified mutations of MSX2 in non-syndromic PFM and demonstrated genetic heterogeneity [10].
• Our findings contrast with the only described MSX2 homeodomain mutation (P148H), associated with craniosynostosis, that binds with enhanced affinity to the same target [11].
• Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification [11].
• The human MSX2 gene localizes to chromosome 5, and a polymorphic marker in the MSX2 intron segregates in a kindred with the disorder with no recombination [12].
• Moreover, a histidine substitutes for a highly conserved proline at position 7 of the MSX2 homeodomain exclusively in affected members [12].

Chemical compound and disease context of MSX2

• MSX2 overexpression inhibits gemcitabine-induced caspase-3 activity in pancreatic cancer cells [2].
• We used cDNA microarray analysis to identify the F. ananassa Nerolidol Synthase1 (FaNES1) gene in cultivated strawberry and showed that the recombinant FaNES1 enzyme produced in Escherichia coli cells is capable of generating both linalool and nerolidol when supplied with geranyl diphosphate (GPP) or farnesyl diphosphate (FPP), respectively [13].
• The GGPPSase expressed in Escherichia coli catalyzes the GGPP formation (240 nmol/min/mg) from FPP and isopentenyl diphosphate [14].
• PFM (using continuous-infusion cisplatin) produced a high response rate but resulted in an high incidence of low-grade peripheral neuropathy [15].
• Regulation of Msx2 gene expression by steroid hormones in human nonmalignant and malignant breast cancer explants cultured in vitro [16].

Biological context of MSX2

• One of the proteins known to be involved in skull development is the MSX2 homeobox protein [17].
• The molecular basis of Boston-type craniosynostosis: the Pro148-->His mutation in the N-terminal arm of the MSX2 homeodomain stabilizes DNA binding without altering nucleotide sequence preferences [18].
• We present a third family with PFMCCD, comprising four affected individuals in three generations, and demonstrate that a heterozygous tetranucleotide duplication in the MSX2 homeobox gene (505_508dupATTG) segregates with the phenotype [1].
• In situ hybridization studies on first trimester human placental sections reveal that MSX2 and MOX2 are expressed predominantly in the cytotrophoblast cell layer [19].
• The homeobox genes MSX2 and MOX2 are candidates for regulating epithelial-mesenchymal cell interactions in the human placenta [19].

Anatomical context of MSX2

• Our observations highlight the role of MSX2 in clavicular development and the importance of radiological examination of the clavicles in subjects with PFM [1].
• In term placenta, MSX2 and MOX2 are expressed in the syncytiotrophoblast [19].
• AIM: To evaluate the effect of MSX2 on gemcitabine-induced caspase-3 activation in pancreatic cancer cell line Panc-1.METHODS: Using V5-tagged MSX2 expression vector, stable transfectant of MSX2 was generated from Panc-1 cells (Px14 cells) [2].
• However, introduction of Smad1 into lymphocytes made the cells competent to regulate MSX2 mRNA after BMP4 treatment [20].
• To test this possibility, we isolated a near full-length human MSX-2 cDNA and tested its activities in two cell systems, i.e. fibroblast and myoblast [21].

Associations of MSX2 with chemical compounds

• MSX2 promotes vaginal epithelial differentiation and wolffian duct regression and dampens the vaginal response to diethylstilbestrol [22].
• 3. Each of these three loci was co-amplified with the autosomal gene MSX2 using Cy5-labelled primers and the products separated by electrophoresis in polyacrylamide gels [23].
• GGTase-I discriminates against farnesyl diphosphate (FPP) at the product turnover step through the inability of a 15-C FPP to displace the 20-C prenyl-peptide product [24].
• CRS2 co-sediments with group II intron RNA during centrifugation of stroma through sucrose gradients, suggesting that CRS2 facilitates splicing via direct interaction with intron RNA [25].
• Green fluorescent protein localization experiments suggest that a change in subcellular localization led to the FaNES1 enzyme encountering both GPP and FPP, allowing it to produce linalool and nerolidol [13].

Physical interactions of MSX2

• In this study, both wild-type and mutant Msx2 were shown to specifically bind to a DNA sequence previously identified as a high-affinity binding site for the related homeodomain protein Msx1 [26].

Regulatory relationships of MSX2

• Our data support a model by which BMP4 induces programmed cell death via an Msx2-mediated pathway and provide direct functional evidence that Msx2 expression is a regulator of this process [27].
• Dlx2 activates the Msx2 promoter in several cell lines and binds DNA as a monomer and dimer [28].
• Msx2 is a mammalian homeodomain protein that is expressed during craniofacial development [26].
• The role of BMP-2 may be through inducing osteoblastic differentiation of VSMCs through induction of MSX-2, or by inducing apoptosis of VSMCs, a process thought critical in the initiation of vascular calcification [29].

Other interactions of MSX2

• Homeobox genes MSX1 and MSX2 are expressed in presumptive dental tissues at the stage of initiation of tooth development [30].
• PFMCCD is indeed aetiologically distinct from CCD, which is caused by mutations in the RUNX2 gene, but allelic with isolated PFM, in which MSX2 mutations were previously identified [1].
• Craniosynostosis associated with ocular and distal limb defects is very likely caused by mutations in a gene different from FGFR, TWIST, and MSX2 [31].
• A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis [12].
• Mutation analysis of the ALX4 gene in three unrelated FPP families without the MSX2 mutation identified mutations in two families, indicating that mutations in ALX4 could be responsible for these skull defects and suggesting further genetic heterogeneity of FPP [4].

Analytical, diagnostic and therapeutic context of MSX2

• Sequence analysis further showed that in four out of five families an MSX2 mutation was responsible for the skull defect [17].
• To examine BMP target genes, the mRNA expression of ID1, ID3, and MSX2 was determined by quantitative real-time PCR [20].
• RESULTS: The RT-PCR screen identified expression of DLX4, HB9, HB24 and MSX2 in the normal colon [32].
• To understand the control of gene expression by these factors, chromatin immunoprecipitation (ChIP) assays identified Msx2 as a downstream target of Dlx2 and Lef-1 [28].
• In this study, analysis of FPP synthase activity and protein in fractionated rat liver together with immunofluorescent and immunoelectron microscopy studies demonstrated unequivocally that FPP synthase is largely localized in peroxisomes [33].

References