Disease relevance of NEUROD1

• RESULTS: There was no evidence of linkage with the markers for NEUROD1 and PAX4 either with MODY or late-onset Type II diabetes [1].
• Our study also suggests that NEUROD1 is not a candidate gene in gestational diabetes mellitus (GDM) [2].
• Neuroectodermal tumor cell lines derived from other sites (e.g., neuroblastoma and retinoblastoma) expressed NeuroD and ACHAETE SCUTE family members [3].
• In the present study, we examined the specific roles of PKCbeta1 and beta2 in growth control in human breast cancer cell lines [4].
• Association of the NEUROD Ala45Thr polymorphism with Type 1 diabetes mellitus (DM) has been found in some but not all populations [5].
• These data support the view that NEUROD1 methylation is a chemosensitivity marker in estrogen receptor-negative breast cancer [6].

Psychiatry related information on NEUROD1

• BACKGROUND: We have previously reported an increase in symptoms of anxiety in patients with posttraumatic stress disorder (PTSD) following administration of the beta 2-antagonist yohimbine, which stimulates brain norepinephrine release [7].
• In this study, the distribution and concentration of beta1, beta2, and alpha2 adrenergic receptors were examined in the frontal cortex, hypothalamus, and cerebellum of Alzheimer's disease (AD) and age-matched control human brains by receptor autoradiography [8].
• Beta 2-receptor density on mononuclear blood cells in patients suffering from neuroleptic-induced akathisia (NIA) [9].
• Effects of beta 1- and beta 2-blockade on blood pressure and sympathetic responses to flight phobia stress [10].
• In Parkinson's disease and dementia with Lewy bodies, striatal deficits in alpha6 (91 and 59% respectively, P < 0.01) and beta3 (72 and 75%, P < 0.05) tended to be greater than for alpha4 and beta2 (50-58%, P < 0.05) [11].

High impact information on NEUROD1

• The latter include peptides specific for the alpha 7, alpha 3 beta 2, and alpha 3 beta 4 nicotinic receptor subtypes [12].
• Further analyses reveal three rules for NLS recognition by Kap beta 2: NLSs are structurally disordered in free substrates, have overall basic character, and possess a central hydrophobic or basic motif followed by a C-terminal R/H/KX(2-5)PY consensus sequence [13].
• The structure of Kap beta 2 (also known as Transportin) bound to one of its substrates, the NLS of hnRNP A1, that we report here explains the mechanism of substrate displacement by Ran GTPase [13].
• Our findings suggest that deficient binding of NEUROD1 or binding of a transcriptionally inactive NEUROD1 polypeptide to target promoters in pancreatic islets leads to the development of type 2 diabetes in humans [14].
• The avidity of integrin CR3 (also known as alpha M beta 2, Mac-1, Mo-1, and CD11b/CD18) may be reversibly altered without changes in the number of cell surface receptors [15].

Chemical compound and disease context of NEUROD1

• Hypokalemia from beta2-receptor stimulation by circulating epinephrine [16].
• METHODS: RAR-beta2 expression was studied by reverse transcription-polymerase chain reaction (RT-PCR) analysis in eight breast cancer cell lines that were either treated with the demethylating agent 5-aza-2'-deoxycytidine and subsequently with all-trans-retinoic acid (ATRA) or left untreated [17].
• Furthermore, murine beta2 integrin mRNA was found to be significantly induced during hypoxia in vivo [18].
• Only aCL found in autoimmune disease require the participation of the phospholipid binding plasma protein beta2 glycoprotein I (beta2GPI) for antibody binding and now are called anti-beta2GPI [19].
• Some studies suggest that beta 2-blockade may reduce platelet cAMP and enhance aggregability in vitro; other studies show that propranolol attenuates platelet aggregability, particularly in patients with ischemic heart disease [20].

Biological context of NEUROD1

• Some studies have reported an association between a nonsynonymous Ala(45)Thr (+182G-->A) single nucleotide polymorphism (SNP) in NEUROD1 and type 1 diabetes, but this result has not been consistently found [21].
• Surprisingly, the presence of NEUROD1, NEUROD2 and ATH2 transcripts was found by reverse transcriptase polymerase chain reaction (RT-PCR) analysis in first trimester placentabed [22].
• BACKGROUND: NEUROD1 encodes a transcription factor expressed in the endocrine pancreas, and involved in beta-cell development, function and mechanisms of apoptosis [23].
• The NEUROD2 transactivation data fit with the spatial expression pattern of NEUROD1 and NEUROD2, since they are expressed in endovascular trophoblasts [24].
• The basic helix-loop-helix (bHLH) transcription factors NEUROD1, NEUROD2 and ATH2 are expressed during first trimester human placental development [24].

Anatomical context of NEUROD1

• The proneural genes NEUROD1 and NEUROD2 are expressed during human trophoblast invasion [22].
• No NEUROD message was detected in glial tumors or cell lines [3].
• Polymorphic variations in the neurogenic differentiation-1, neurogenin-3, and hepatocyte nuclear factor-1alpha genes contribute to glucose intolerance in a South Indian population [25].
• The HLH domain is also the characteristic of the bHLH family, which implied a large number of PTDs could be discovered in this family to fit different purposes, and some of them could be directly recruited to penetrate cell membrane according to their crucial roles in development such as NeuroD and Ngn3 [26].
• Disruption of the gene encoding BETA2/NeuroD1 leads to severe abnormalities of the developing mouse central nervous system as well as the peripheral nervous system [27].

Associations of NEUROD1 with chemical compounds

• In conclusion, we observed a combined effect of variations in NEUROD1, NEUROG3, and TCF1 in contributing to overall glucose intolerance in a South Indian population [25].
• Four diabetic patients carried the homozygous mutation (Thr/Thr) in the NeuroD1 gene and 3 patients carried the homozygous mutation (Trp/Trp) in the Pax4 gene, while both homozygous mutations were not detected in the control subjects [28].
• BETA 2/NEUROD1 is a key regulator of pancreatic islet morphogenesis and insulin gene transcription [29].
• Neuronal nicotinic acetylcholine receptors are pentamers of homomeric or heteromeric combinations of alpha (alpha2-alpha10) and beta (beta2-beta4) subunits, which have different pharmacological and biophysical properties and locations in the brain [30].
• MCP-1 stimulated beta1 integrin-dependent, but not beta2 integrin-dependent cell adhesion in a time-dependent manner [31].
• NeuroD1 is inactive in baseline prostate cell lines and BPHs, whereas it is actively expressed in cAMP-treated EPN, PC3, and DU145 cells [32].

Physical interactions of NEUROD1

• We have identified an INSM1 binding site in the neuroD/beta2 promoter and demonstrated transcriptional repressor activity of INSM1 by transient transfection assay [33].
• Mutational analysis of a proximal enhancer in the secretin gene identified several cis-acting elements in addition to the E-box binding site for BETA2 [34].
• ISL1 physically interacts with BETA2 to promote insulin gene transcriptional synergy in non-beta cells [35].
• Previous studies have shown that PDX-1 can interact synergistically with E47 and beta2 to activate the rat insulin 1 promoter [36].
• These findings indicate that in addition to induction of CD11a/CD18-mediated cell adhesion, the ICAM-2 peptide may also serve as a "trigger" for high avidity ligand binding of other beta 2 integrins [37].

Enzymatic interactions of NEUROD1

• Insulin receptor beta subunit autophosphorylation occurs in an intramolecular trans-reaction in which one beta subunit phosphorylates the adjacent beta subunit within an alpha 2 beta 2 holoreceptor complex (Frattali, A. L., Treadway, J. L., and Pessin, J. E. (1992) J. Biol. Chem. 267, 19521-19528) [38].
• In the present study we identified phospholipase C gamma 2 (PLC gamma 2) as one of the major proteins that was phosphorylated on tyrosine in response to beta 2 integrin activation [39].

Co-localisations of NEUROD1

• The NeuroD1/BETA2 sequences essential for insulin gene transcription colocalize with those necessary for neurogenesis and p300/CREB binding protein binding [40].

Regulatory relationships of NEUROD1

• Cyclin D1 co-operates with INSM1 and suppresses neuroD/beta2 promoter activity [33].
• In contrast, neutrophil adhesion to fibronectin was completely inhibited by anti-beta2 integrins, suggesting that S100A9-induced specific activation of beta2 integrin is essential to neutrophil adhesion [41].
• The NeuroD1-containing heterodimers specifically recognize and activate transcription from the POMC promoter E box that confers transcriptional specificity [42].
• Interestingly, the NeuroD1 heterodimers activate transcription in synergy with Ptx1, a Bicoid-related homeodomain protein, which also contributes to corticotroph specificity of POMC transcription [42].
• BETA2 activates transcription from the upstream glucokinase gene promoter in islet beta-cells and gut endocrine cells [43].

Other interactions of NEUROD1

• Here we show that Finb/RREB-1 can associate with BETA2 to enhance its transcription-activating function [34].
• Separate expression of BETA2, E2A, or PDX1 led to modest (<10-fold) activation of the insulin promoter, whereas co-expression of the three proteins produced synergistic, high level activation (160-fold) [44].
• Mutation screening showed single nucleotide polymorphisms, several of which resulted in amino acid substitutions: NEUROD1, Ala45Thr; PAX4, Pro321His and Pro334Ala [1].
• NEUROD1 expression is found in interstitial and endovascular invasive cells, while NEUROD2 expression is observed mainly in endovascular invasive cells, respectively [22].
• A chromatin immunoprecipitation assay confirmed that in vivo INSM1 is situated on the promoter region of the neuroD/beta2 gene [33].

Analytical, diagnostic and therapeutic context of NEUROD1

• In situ hybridization and immunocytochemical analyses of adult retina showed that NeuroD transcripts and NeuroD immunoreactivity are predominantly localized to the outer nuclear layer which contains the photoreceptors [45].
• Immunohistochemistry for NeuroD1 was also performed in 25 PA [46].
• Our case-control study suggests that the Ala45 variant of BETA2/NeuroD1 may be associated with T1DM in Caucasians (or in linkage disequilibrium with a causative variant) [47].
• Co-immunoprecipitation also supported that ISL1 and BETA2 appear in one complex and this physical interaction mediates the synergy between these two proteins [35].
• Ala45Thr polymorphism of the NEUROD1 gene and diabetes susceptibility: a meta-analysis [48].

References