Disease relevance of PBX1

• The t(1;19)(q23;p13) results in consistent fusion of E2A and PBX1 coding sequences in acute lymphoblastic leukemias [1].
• E2A-PBX1 is a chimeric gene formed by the t(1;19)(q23;p13.3) chromosomal translocation of pediatric pre-B-cell leukemia [2].
• Meis1, a PBX1-related homeobox gene involved in myeloid leukemia in BXH-2 mice [3].
• Molecular evidence of E2A/PBX1 fusion transcripts was also observed in a patient in whom a t(1;19) was not detected cytogenetically and in one patient with subclinical levels of minimal residual disease before overt clinical relapse [1].
• Fusion with E2A alters the transcriptional properties of the homeodomain protein PBX1 in t(1;19) leukemias [4].

Psychiatry related information on PBX1

• Short-term administration of PRL and even long-term hyperprolactinemia in animals increases REM sleep [5].
• Data were examined using the methodology described in the original report, consisting of averaging across individual nights PRL levels during REM and non-REM sleep stages as well as using a detailed spike by spike analysis of each individual pair of hormonal and sleep profiles [6].
• A paradoxical rise in plasma PRL values was observed in anorexia nervosa patients during the course of a gonadotropin-releasing hormone infusion [7].
• A sleep-onset rapid eye movement period occurred in all of the patients, and this abnormal phenomenon characteristic of narcolepsy was considered to be related to the suppression of GH release at the sleep onset and to the decrease of plasma PRL levels during the early part of sleep [8].
• Plasma GH and PRL measurements in these four conditions revealed an effect of sleep deprivation independent of the presence or absence of melatonin [9].

High impact information on PBX1

• Functional studies validated Sprouty2 and PBX1, among others, as FoxO-regulated mediators of endothelial cell morphogenesis and vascular homeostasis [10].
• These data indicate that the chimeric homeodomain protein E2A-PBX1 paradoxically induces both proliferation and apoptosis in lymphoid cells, suggesting an in vivo association between nuclear oncogene-induced cell cycle progression and programed cell death [11].
• E2A-PBX1 also markedly altered lymphoid development in pretumorous animals, reducing the number of thymocytes and bone marrow B lineage progenitors to 20% of normal levels [11].
• extradenticle, a regulator of homeotic gene activity, is a homolog of the homeobox-containing human proto-oncogene pbx1 [12].
• Two E2A-pbx1 transcripts have been cloned [13].

Chemical compound and disease context of PBX1

• Analysis of PBX1 as a candidate gene for type 2 diabetes mellitus in Pima Indians [14].
• The foregoing disparity suggests the possibility of a role for estrogen in enhancing the effect of hypothyroidism on PRL release.(ABSTRACT TRUNCATED AT 400 WORDS)[15]
• Plasma GH, PRL, and cortisol levels rose significantly in response to insulin-induced hypoglycemia [16].
• The catecholamine dopamine (D) is involved in the regulation of LH and PRL secretion, whereas a dysregulated noradrenergic system may contribute significantly to symptoms encountered in affective disorders [17].
• These data suggest that men with serum PRL levels above 50 ng/ml maintain a normal diurnal pattern of serum testosterone at a lower set point, and demonstrate hypogonadism with reduced urinary LH excretion and NPT [18].

Biological context of PBX1

• Chromosome in situ hybridizations demonstrated that the PBX genes are not clustered but map to separate chromosomal loci: PBX1, 1q23; PBX2, 3q22-23; PBX3, 9q33-34 [19].
• Differences in their amino and carboxy termini may modulate their activities, mediated in part by differential splicing and, for PBX1, protein fusion following t(1;19) chromosomal translocation [19].
• Here we demonstrate that the homeodomains encoded by PBX1, as well as by the highly related PBX2 and PBX3 genes, bind the DNA sequence ATCAATCAA [2].
• Despite the presence of HOXB1 and PBX1, this enhancer fails to activate reporter gene expression in retinoic acid-treated P19 cell monolayers [20].
• We previously showed that HOXB1 and PBX1 activate transcription from the b1-ARE by binding to sequences required for the expression of a reporter gene in rhombomere 4 in vivo [21].

Anatomical context of PBX1

• Expression of PBX2 or PBX3 was not restricted to particular states of differentiation or development, as mRNA transcripts of these genes were detected in most fetal and adult tissues and all cell lines, unlike PBX1, which is not expressed in lymphoid cell lines [19].
• The prognostically important 1;19 chromosomal translocation can alter the E2A gene on chromosome 19p13 in childhood B-cell precursor acute lymphoblastic leukemia (ALL), leading to formation of a fusion gene (E2A-PBX1) that encodes a hybrid transcription factor with oncogenic potential [22].
• Earlier, we found that expression of E2A-Pbx1 causes malignant transformation of NIH 3T3 fibroblasts and induces myeloid leukemia in mice [2].
• We sequenced the genomic fusion between E2A and PBX1 in 22 preB acute lymphoblastic leukemias and two cell lines [23].
• PBX1 intracellular localization is independent of MEIS1 in epithelial cells of the developing female genital tract [24].

Associations of PBX1 with chemical compounds

• The human proto-oncogene PBX1 codes for a homeodomain containing protein that modulates expression of several genes, including those contributing to regulation of insulin action and glucose metabolism [14].
• Comparison of the frequencies of the polymorphisms between affected and unaffected Pima Indians did not detect any significant differences, indicating that mutations in PBX1 do not explain the linkage of 1q with type 2 diabetes in this population [14].
• We detected 16 single nucleotide polymorphisms in PBX1 including one causing a glycine to serine substitution at residue 21 [14].
• Critical role for a single leucine residue in leukemia induction by E2A-PBX1 [25].
• Enhanced autophagic cell death in expanded polyhistidine variants of HOXA1 reduces PBX1-coupled transcriptional activity and inhibits neuronal differentiation [26].

Physical interactions of PBX1

• These biologic effects of HOXB6 were largely dependent on DNA binding but independent of direct interaction with PBX1 [27].
• The t(1;19) translocation results in the production of a chimeric transcription factor containing the N-terminal transactivation domain of E2A fused to the C-terminal DNA-binding homeodomain of Pbx1 [28].
• Expanded HOXA1 variants exhibited reduced PBX1-coupled transcriptional activity through a regulatory enhancer of HOXB1 [26].
• Pre-B cell leukemia transcription factor 1 (PBX1) encodes a homeodomain containing protein that is essential for pancreatic development and interacts with insulin promoter factor 1 to regulate insulin secretion [29].

Regulatory relationships of PBX1

• We find HoxA9-mediated CYBB-transcription requires Pbx1 but is inhibited by Meis1 [30].
• We report here that experimental induction of E2a-Pbx1 enhances expression of BMI-1, a lymphoid oncogene whose product functions as a transcriptional repressor of the INK4A-ARF tumor suppressor locus [31].
• The positive interaction between DAX1 and SF-1 in regulating PBX1 may be an important mechanism in this process [32].

Other interactions of PBX1

• We map a site of interaction with HDAC1 to the PBX1 N terminus and show that the PBX partner is required for repression by the HOX-PBX complex [20].
• However, PBX1 exogenously introduced into COL5A2-negative cells cannot stimulate FPB-driven transcription unless co-expressed with PREP1 [33].
• Heterodimerization with PBX1 appears to be essential for nuclear localization of both PREP2 and PBX1 [34].
• Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1 [35].
• Molecular studies showed E2A-PBX1 abnormalities in all examined cases (12 of 12) with the t(1;19), including the case lacking CD9 data [36].

Analytical, diagnostic and therapeutic context of PBX1

• In all PCR-positive cases the junction of E2A and PBX1 coding sequences occurred at precisely the same location as demonstrated by hybridization of PCR products with a fusion site-specific detection oligonucleotide [1].
• Sequence analysis showed an identical insertion of 27 bp at the E2A/PBX1 junction of the variant RNA species, the translation of which would result in the replacement of Val478 by 10 amino acids [37].
• E2A-PBX1 chimeric transcript status at end of consolidation is not predictive of treatment outcome in childhood acute lymphoblastic leukemias with a t(1;19)(q23;p13): a Pediatric Oncology Group study [38].
• By means of reverse transcriptase-polymerase chain reaction analysis, we detected E2A/PBX1 fusion transcripts in KMO-90 cells [39].
• Correlation of cytoplasmic Ig mu (C mu) and E2A-PBX1 fusion transcripts in t(1;19) B lineage ALL: discrepancy in C mu detection by slide immunofluorescence and flow cytometry [40].

References