Disease relevance of HNRPD

• Together, these data suggest a mechanism whereby reduced cytoplasmic levels of AUF1 in MNT1 melanoma cells may lead to IL-10 overexpression, with deleterious consequences for tumor surveillance and rejection [1].
• The AUF1 modifications as a result of uremia were reversed by treatment with R-568 to those of normal rats [2].
• In the present study, we demonstrate a strong correlation between increased cytoplasmic expression of both AUF1 and HuR with urethane-induced neoplasia and with butylated hydroxytoluene-induced compensatory hyperplasia in mouse lung tissue [3].
• We discuss: (a) the types of 3'-UTR sequences involved in mRNA stability, (b) AUF1, HuR and other proteins that bind to these sequences to either stabilize or destabilize the target mRNAs, and (c) the potential role of the 3'-UTR mediated mRNA stability in heart failure, myocardial infarction and hypertension [4].
• Conduction to the parietal cortex (T12-P37 interpeak latency) worsened in both the symptomatic men and the boys with preclinical adrenomyeloneuropathy [5].

High impact information on HNRPD

• Endotoxic shock in AUF1 knockout mice mediated by failure to degrade proinflammatory cytokine mRNAs [6].
• We show that AUF1 normally functions to protect against the lethal progression of endotoxemia [6].
• Analysis of both endogenous and chimeric GADD45alpha mRNA revealed that in untreated cells AUF1 strongly reduced GADD45alpha mRNA stability, whereas TIAR potently inhibited GADD45alpha translation [7].
• Here, two RNA binding proteins, the mRNA decay-promoting AUF1 and the translational suppressor TIAR, were found to interact specifically with the 3' untranslated region (UTR) of the GADD45alpha mRNA in HeLa cells [7].
• After genotoxic stress, AUF1 and TIAR dissociated from the GADD45alpha mRNA, thereby allowing coordinated elevations in both GADD45alpha mRNA half-life and translation rate, respectively [7].

Chemical compound and disease context of HNRPD

• Regulation of the Epstein-Barr virus C promoter by AUF1 and the cyclic AMP/protein kinase A signaling pathway [8].
• METHODS: 40 patients with vitamin B12 deficiency neurological syndromes with low serum vitamin B12 and high homocysteine levels were subjected to a detailed motor and sensory nerve conduction studies and pattern reversal VER (P100), SSEP (P37) after stimulation of the posterior tibial nerve and median nerve (N 20) were obtained bilaterally [9].
• Immunohistochemical studies revealed AUF1 to be expressed in the cytoplasm of RA synovial tissue as compared with nuclear staining in osteoarthritis and normal synovium, particularly in macrophages of the lining layer and in fibroblasts of the sublining areas [10].

Biological context of HNRPD

• Use of two of the coding exons is determined by alternative splicing of the HNRPD mRNA [11].
• Sequence analysis of the human HNRPD gene shows that the protein is encoded by eight exons and that two additional exons specify sequences in the 3' UTR [11].
• The results demonstrated that coordinated regulation of mRNA stability by HuR and AUF1 proteins contributes to the observed increase in ATF3 expression following amino acid limitation [12].
• Therefore, calcineurin regulates AUF1 posttranslationally in vitro and PTH gene expression in vivo but still allows its physiological regulation by calcium and phosphate [13].
• However, two-dimensional gels showed posttranslational modification of AUF1 that included phosphorylation [13].

Anatomical context of HNRPD

• There is no PT cell line, but in HEK 293 cells the 63-nt element is recognized as an instability element, and RNA interference for AUF1 decreased human PTH secretion in cotransfection experiments [13].
• Finally, we find that the ARE-binding protein AUF1 comprises the major ARE-binding activity in cytoplasmic extracts of normal melanocytes [1].
• AUF1 protein, a negative regulator of ARE mRNA stability, displayed strong expression in thymus and spleen cells within lymphocytic cells, moderate expression in the epithelial linings of lungs, gonadal tissues, and nuclei of most neurons in the brain, and little expression in the other tissues [14].
• Tristetraprolin, a negative regulator of ARE mRNA stability, displayed a largely non-overlapping tissue distribution with AUF1 and was predominantly expressed in the liver and testis [14].
• Previous genomic cloning combined with FISH and Southern analyses of a panel of monochromosomal mouse/human or hamster/human somatic cell hybrids localized two AUF1 loci to human 4q21.1-q21.2 and Xq12 (B. Wagner et al., 1996, Genomics 34: 219-222) [15].

Associations of HNRPD with chemical compounds

• In contrast, the interaction of AUF1 with the ATF3 mRNA is decreased in histidine-deprived cells relative to control cells [12].
• Lactate dehydrogenase is an AU-rich element-binding protein that directly interacts with AUF1 [16].
• A "liaison dangereuse" between AUF1/hnRNPD and the oncogenic tyrosine kinase NPM-ALK [17].
• Interaction of RNA binding proteins, such as the cloned adenosine + uridine-rich element, binding factor, AUF1, with eight AUUUA motifs in the human GM-CSF mRNA 3'-untranslated region (GM-3'-UTR) has been implicated in regulating transcript stability [18].
• This site appears to involve a series of amino acids immediately after the third cysteine residue beginning with P37 [19].

Physical interactions of HNRPD

• Thus, AUF1 binds to multiple destabilizing elements within the 3'-UTR that participate in the rapid turnover of the PEPCK mRNA [20].
• The effect of the calcimimetic on PTH gene expression was posttranscriptional and correlated with differences in protein-RNA binding and posttranslational modifications of the trans acting factor AUF1 in the PT [2].
• We demonstrate that all four AUF1 protein isoforms bind directly and strongly to initiation factor eIF4G at a C-terminal site regardless of AUF1 interaction with the ARE [21].
• As judged by RNA-gel mobility shift assays, this rapid degradation of SH2D1A mRNA was due to a balance in binding of the factors AUF1 and HuR to its 3' UTR [22].
• We focus initially on the basic concepts in mRNA stability with the trans-acting factors AUF1 (destabilizing) and HuR (stabilizing) [23].

Regulatory relationships of HNRPD

• Further studies indicated that stimulation of the NMDA receptor induces a downregulation in AUF1 levels stabilising the alpha(2) mRNA transcripts [24].

Other interactions of HNRPD

• Amino acid limitation caused a slightly elevated mRNA level for HuR and AUF1 mRNA [12].
• Increased interleukin-10 mRNA stability in melanoma cells is associated with decreased levels of A + U-rich element binding factor AUF1 [1].
• A nuclear matrix-associated factor, SAF-B, interacts with specific isoforms of AUF1/hnRNP D [25].
• These modifications in AUF1 correlate with changes in protein-PTH mRNA binding and PTH mRNA levels [2].
• Based on these and other data, we propose a model for the molecular interactions of AUF1 that involves translation-dependent displacement of AUF1-PABP complexes from ARE-mRNAs with possible unmasking of the poly(A) tail [21].
• The AUF1 effect on iNOS expression is dependent on the iNOS 3'-untranslated region sequence, as demonstrated in transfection experiments with a reporter mRNA [26].

Analytical, diagnostic and therapeutic context of HNRPD

• In situ hybridization analyses using P1 clones as probes identified the 4q21.1-q21.2 and Xq12 regions as the locations of the AUF1 genes [27].
• RNA gel shift analyses established that AUF1 (hnRNP D) binds to the PCK-7, PCK-6, and PCK-2 segments with high affinity and specificity [20].
• Tibial somatosensory evoked potential intraoperative monitoring: recommendations based on signal to noise ratio analysis of popliteal fossa, optimized P37, standard P37, and P31 potentials [28].
• Anti-AUF1 immunoblotting showed significantly higher levels of two AUF1 protein isoforms and lower levels of one in cord than in adult MNC or 5637 extracts [18].
• An RNA titration recruitment assay revealed that alphaCPs were quantitatively incorporated into the alpha-complex in the absence of associated AUF1 and hnRNP K [29].

References