Disease relevance of MAPRE2

• As the expression level of the RP1 gene in activated T cells and a spectrum of tumor-derived cell lines correlates with the proliferative status of the cells, members of the EB1-like gene family may not only be involved in the tumorigenesis of colorectal cancers but may also play a role in the proliferative control of normal cells [1].
• Overexpression of EB1 in human esophageal squamous cell carcinoma (ESCC) may promote cellular growth by activating beta-catenin/TCF pathway [2].
• Expression of an EBV activatable early promoter depends on the presence of both EB1 and EB2 [3].
• Recently we identified the gene responsible for the RP1 form of autosomal dominant retinitis pigmentosa (adRP) at 8q11-12 and found two different nonsense mutations in three families previously mapped to 8q [4].
• Further studies will determine whether missense changes in the RP1 gene are associated with disease, whether mutations in other regions of RP1 can cause forms of retinal disease other than adRP and whether the background variation in either the mutated or wild-type RP1 allele plays a role in the disease phenotype [4].

Psychiatry related information on MAPRE2

• A mutation that abolishes upstream stimulatory factor binding, either alone or in combination with the alpha EB1 mutation, reduces basal activity of the promoter to approximately 21% of control levels in alpha T3-1 cells and abolishes the decrease in promoter activity seen when Id is overexpressed [5].

High impact information on MAPRE2

• Here we have identified two mutations in a novel retina-specific gene from chromosome 8q that cause the RP1 form of autosomal dominant RP in three unrelated families [6].
• EB1 is located on microtubules of the mitotic spindle and is important in spindle assembly [7].
• EB1 family proteins may have a general role in linking the microtubule cytoskeleton to cortical polarity determinants [8].
• Spindles cotton on to junctions, APC and EB1 [9].
• Integrin-mediated adhesion orients the spindle parallel to the substratum in an EB1- and myosin X-dependent manner [10].

Chemical compound and disease context of MAPRE2

• Although Hafnia alvei was a major component of the Enterobacteriaceae flora in all foods tested and a strong AHL producer, the signal molecules produced by H. alvei strain EB1 did not influence protease production by Pseudomonas fluorescens strain 395 in vitro [11].

Biological context of MAPRE2

• We also determined that the EB1 family protein-binding regions are amino acids 2781-2820 and 18-111 of APC and p150glued, respectively [12].
• The rapid up-regulation of RP1 mRNA in properly activated T cells suggests that this gene might belong to the immediate/early gene family, which controls the signal transduction cascade downstream of the TCR [1].
• The RP1 gene was found to be encoded on chromosome 18q21, a locus which is altered or deleted in up to 50% of all patients with colorectal cancer [13].
• Data obtained with highly conserved yeast homologues suggest that the EB1/RP1 protein family promotes cytoplasmic microtubule dynamics and contributes to the sensor mechanism controlling the cytokinesis checkpoint during mitosis [13].
• We report that overexpression of EB1 in the ESCC line EC9706 significantly promotes cell growth, whereas suppression of EB1 protein level by RNA interference significantly inhibited growth of esophageal tumor cells [2].

Anatomical context of MAPRE2

• CLASP1 and CLASP2 bind to EB1 and regulate microtubule plus-end dynamics at the cell cortex [14].
• EB1 family proteins are evolutionarily conserved proteins that bind microtubule plus-ends and centrosomes and regulate the dynamics and organization of microtubules [12].
• When EB1 family proteins were overexpressed, they associated with the entire microtubule cytoskeleton [15].
• Immunoprecipitation suggested that APC and EB1 were not associated in cultures of HCT116 cells arrested in mitosis [16].
• Mutations in RP1 are a common cause of dominant retinitis pigmentosa (RP), but the mechanism by which the identified mutations lead to photoreceptor cell death and blindness has not been determined [17].

Associations of MAPRE2 with chemical compounds

• Members of the cyclic AMP response element binding protein family (CREB1 and CREB2) could be identified as transcription factors binding specifically within the RP1 promoter sequence [13].
• EB1 did not localize to kinetochores lacking attached kinetochore microtubules in prophase or early prometaphase, or upon nocodazole treatment [18].
• Time-lapse analysis of p150(Glued) revealed targeting to the plus ends of growing microtubules, requiring the NH2-terminal cytoskeleton-associated protein-glycine rich domain, but not EB1 or CLIP-170 [19].
• Recruitment of EB1 to microtubules required Ca(2+) influx, but was independent of PKC [20].
• Although it increases the amount of chloramphenicol acetyltransferase enzyme expressed from the chimeric pMCAT gene, EB2 is not a promiscuous trans-activator of gene expression and does not positively regulate its own expression from promoter PM [21].

Physical interactions of MAPRE2

• RP1, a new member of the adenomatous polyposis coli-binding EB1-like gene family, is differentially expressed in activated T cells [1].

Other interactions of MAPRE2

• The MAPRE genes encode the EB1 family proteins [22].
• An unexpected reciprocal cross-inhibition of soluble antigen antibody complex binding was observed between antibodies reacting to distinct determinants, i.e. for NA27 towards NA39/EB2 and for NA71 towards EB1/EB3 [23].
• 60S APC did not contain EB1 or diaphanous, proteins that have been reported to interact with APC and are implicated in microtubule plus end stabilization [24].
• EB1 is the first gene on chromosome 20 found to fuse with MLL [25].

Analytical, diagnostic and therapeutic context of MAPRE2

• Using the SDS-polyacrylamide immunoblotting technique, it was shown that one epitope (shared with human chorionic somatomammotropin) detected by EB1 (or EB3) antibody was expressed to a similar extent by both the N-terminal (15 K) and C-terminal (7 K) polypeptides [26].
• Southern blot analysis indicated that a rearrangement of the MLL gene was involved in the chromosomal abnormality. cDNA panhandle polymerase chain reaction (PCR) identified the fusion transcript, in which MLL exon 6 was fused in-frame with EB1 exon 5 [25].
• RT-PCR was used to amplify illegitimate RP1 transcripts from lymphoblasts [17].
• Immunofluorescence staining demonstrated that the MLL-EB1 fusion proteins were localized in the nuclei [25].
• Site-directed mutagenesis of one of the E-box motifs, EB2, resulted in a 60% reduction in basal reporter gene activity [27].

References