Disease relevance of NXT1

• We explored bacterial RNase P as a drug target using antisense oligomers against the P15 loop region of Escherichia coli RNase P RNA [1].
• Cleavage of p15 protein in vitro by human immunodeficiency virus type 1 protease is RNA dependent [2].
• Beet yellows virus Peanut P21, clump virus P15, Barley stripe mosaic virus gammaB, and Tobacco etch virus HC-Pro, like P19, bind ds-sRNAs size-selectively, while Turnip crinkle virus CP is a size-independent dsRNA-binding protein, which binds long dsRNAs as well as ds-sRNAs [3].
• We have recently reported that the reverse transcription of HIV-1 RNA is markedly enhanced by the association of the gag encoded nucleocapsid p15 protein and cellular topoisomerase 1 [4].
• These results suggest that the p15 protein itself is an effective vaccine and that the adenovirus may be used to mount a non-specific cellular immune response [5].

High impact information on NXT1

• Export of mRNAs is mediated by a conserved heterodimeric transport receptor (known as NXF1-p15 in metazoa) that binds to mRNA cargoes either directly or indirectly by means of adaptor proteins [6].
• In contrast, p27Delta cells proliferated in tolerizing conditions because of Cdk kinase activation and phosphorylation of Smad3, which resulted in no upregulation of p15 [7].
• Structural basis for the recognition of a nucleoporin FG repeat by the NTF2-like domain of the TAP/p15 mRNA nuclear export factor [8].
• TAP-p15 heterodimers have been implicated in the export of mRNAs through nuclear pore complexes (NPCs) [8].
• We find that NXT1 binds directly to Crm1, and that the interaction is sensitive to the presence of Ran-GTP [9].

Biological context of NXT1

• These properties, together with the fact that NXT1 shuttles between the nucleus and the cytoplasm, suggest an active role in nuclear transport [10].
• The critical importance of NXT1 for the nuclear export of poly(A)(+) RNA is emphasized by the finding that specific inhibition of the expression of the Drosophila homolog of human NXT1, by using RNA interference, results in the nuclear accumulation of poly(A)(+) RNA in cultured insect cells [11].
• The structure of the Mtr2-Mex67 NTF2-like domain complex, which overall is similar to those of the human and Saccharomyces cerevisiae homologs, unveils three putative Phe-Gly repeat binding sites, of which one contributes to the heterodimer interface [12].
• Structural similarity in the absence of sequence homology of the messenger RNA export factors Mtr2 and p15 [13].
• Patients with lower pretreatment levels of p15 methylation had a significantly higher response rate [14].

Anatomical context of NXT1

• Formation of Tap/NXT1 heterodimers activates Tap-dependent nuclear mRNA export by enhancing recruitment to nuclear pore complexes [11].
• Immunohistochemical staining for p15 protein in bone marrow biopsies from 8 patients with p15 hypermethylation revealed low or absent expression in 4 patients, which was induced to normal levels during decitabine treatment [15].
• We found that T-lymphocytes accumulate p16 and p15 protein during successive population doublings and display high levels of these proteins as they enter into replicative senescence [16].
• In the thalamus, exogenous and endogenously released NPY can shorten the duration of thalamic oscillations in brain slices from P13 to P15 rats, an in vitro model of absence seizures [17].
• VGLUT1-IR bouton density on Renshaw cells increased until P15 but thereafter decreased because of limited synapse proliferation coupled with the enlargement of Renshaw cell dendrites [18].

Associations of NXT1 with chemical compounds

• The export function of NXT1 is blocked by the addition of leptomycin B, a compound that selectively inhibits the NES receptor Crm1 [10].
• The emergence of partially demethylated epigenotypes and re-establishment of normal p15 protein expression following the initial decitabine courses implicate pharmacologic demethylation as a possible mechanism resulting in hematologic response in MDS [15].
• Bisulfite sequencing of the p15 promoter in marrow DNA during the first cycle of treatment showed heterogeneous allelic demethylation in three responding patients, suggesting ongoing demethylation within the tumor clone, but no demethylation in two nonresponders [19].
• Two agonists, p29 (LLPWTVLTV) and p15 (VLLWTVLTV), were equally stimulatory when loaded onto C1R target cells transfected with wild-type HLA-A2 [20].
• With the exception of animals receiving methamphetamine from P15 to P19, thymus weights were unaffected [21].

Physical interactions of NXT1

• Metazoan NXF1/p15 heterodimers promote export of bulk mRNA through nuclear pore complexes (NPC) [22].

Regulatory relationships of NXT1

• Thus, NXT1 regulates the Crm1-dependent export pathway through its direct interaction with Ran-GTP [10].
• Indeed, NXT1 stimulates nuclear protein export of the NES-containing protein PKI in vitro [10].

Other interactions of NXT1

• These results support the emerging view that NXT1 is a general export factor, functioning on both CRM1-dependent and CRM1-independent pathways of RNA export [23].
• Functional analysis of NXF5 demonstrates binding to RNA as well as to the RNA nuclear export-associated protein p15/NXT [24].
• Furthermore aberrant P15 protein expression was detected in 85% of patients analyzed with P15 gene abnormalities and abnormal P16 expression in 59% with P16 gene abnormalities [25].

Analytical, diagnostic and therapeutic context of NXT1

• Six of six responding patients with pretreatment methylation of p15 or CDH-1 promoters reversed methylation during the first cycle of therapy (methylation-specific PCR), whereas none of six nonresponders showed any demethylation [19].
• Using fluorescent in situ hybridization (FISH) with the probe p15 (D15Z1), we investigated the distribution of the polymorphic 15p signal which has been reported to occur on acrocentric chromosomes in addition to chromosome 15 [26].

References