Disease relevance of KHSRP

• A role for LEDGF/p75 in targeting HIV DNA integration [1].
• Although a direct role in integration has only been demonstrated for LEDGF/p75, to date, each validated cellular co-factor for HIV-1 integration could constitute a promising new target for antiviral therapy [2].
• Deficient p75 low-affinity neurotrophin receptor expression does alter the composition of cellular infiltrate in experimental autoimmune encephalomyelitis in C57BL/6 mice [3].
• Antinuclear autoantibodies in prostate cancer: immunity to LEDGF/p75, a survival protein highly expressed in prostate tumors and cleaved during apoptosis [4].
• RESULTS: Anti-LEDGF/p75 autoantibodies were detected by ELISA in 18.4% of PCa patients and 5.5% of matched controls (P < 0.001) but not in patients with benign prostatic hyperplasia (BPH) [4].

Psychiatry related information on KHSRP

• The lowered folate binding capacity of FBP is not explained by a defect of the FBP1 or FBP2 gene, but most likely occurs as a secondary phenomenon in Rett syndrome [5].

High impact information on KHSRP

• Cells expressing a noncleavable mutant of p75 sustain DeltaPsim and ATP levels during apoptosis, and ROS production in response to apoptotic stimuli is dampened [6].
• Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain [6].
• While cytochrome c release and DNA fragmentation are unaffected by the noncleavable p75 mutant, mitochondrial morphology of dying cells is maintained, and loss of plasma membrane integrity is delayed [6].
• A new regulatory protein, KSRP, mediates exon inclusion through an intronic splicing enhancer [7].
• KSRP is expressed in both neural and non-neural cell lines, although it is present at higher levels in neural cells [7].

Chemical compound and disease context of KHSRP

• Exposure of SN56 cholinergic neuroblastoma cells to dibutyryl cAMP and retinoic acid for 3 days caused their morphologic differentiation along with the increase in choline acetyltransferase activity, acetylcholine content and release, calcium content, and the expression of p75 neurotrophin receptors [8].

Biological context of KHSRP

• Here, we demonstrate that KSRP, a KH domain-containing ARE-BP, is an essential factor for ARE-directed mRNA decay [9].
• A KH domain RNA binding protein, KSRP, promotes ARE-directed mRNA turnover by recruiting the degradation machinery [9].
• Mapping of the binding site revealed KSRP interacting with the most 3'-located AU-rich element (ARE) of the human iNOS mRNA [10].
• In accordance, downregulation of KSRP expression increases iNOS expression by stabilizing iNOS mRNA [10].
• Furthermore, the lens-epithelium-derived growth factor (LEDGF; also known as p75) seems to tether HIV-1 integrase to the chromosomes [2].

Anatomical context of KHSRP

• However, formation of osteoclasts was significantly decreased by the soluble decoy receptor for LIGHT, DcR3, and by blocking antibodies to the p75 component of the TNF receptor [11].
• We describe the isolation of multipotent stem cell-like cells from the adult trunk skin of mice and humans that express the neural crest stem cell markers p75 and Sox10 and display extensive self-renewal capacity in sphere cultures [12].
• All patients receiving more than percentile 75 (p75) of CD34+ cells reached complete chimerism in T lymphocytes by days 21 to 28, compared with 44% among those receiving p75 or fewer cells (P =.046) [13].
• A homolog of FBP2/KSRP binds to localized mRNAs in Xenopus oocytes [14].
• Overexpression of Nrf2 in astrocytes increased survival of co-cultured embryonic motor neurons and prevented motor neuron apoptosis mediated by nerve growth factor through p75 neurotrophin receptor [15].

Associations of KHSRP with chemical compounds

• In CSF, the overall folate binding capacity by the two soluble folate-binding proteins FBP1 and FBP2 (sFBP) was measured using a radioligand binding method for H3-labeled folate [5].
• Many investigations indicate that the survival-promoting signals of neurotrophins are generated by activation of Trk tyrosine kinase receptors and that their death-promoting signals are generated by activation of p75 neurotrophin receptors (p75(NTR)) [16].
• This tristetraprolin-KSRP interaction was enhanced by cytokines and reduced by SB203580 treatment [17].
• Our findings show that NGF secreted by reactive astrocytes induce the death of p75-expressing motor neurons by a mechanism involving nitric oxide and peroxynitrite formation [18].
• Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75-dependent motor neuron apoptosis [19].

Physical interactions of KHSRP

• KSRP is a component of a multiprotein complex that binds specifically to an intronic splicing enhancer element downstream of the neuron-specific c-src N1 exon [7].

Co-localisations of KHSRP

• Several reports have shown that KH-type splicing regulatory protein colocalizes with the polypyrimidine tract-binding protein (PTB), and both RNA-binding proteins seem to interact with the same mRNAs [20].

Regulatory relationships of KHSRP

• Immunodepletion of KSRP enhanced iNOS 3'-UTR RNA stability in in vitro-degradation assays [10].

Other interactions of KHSRP

• Immunoprecipitation analysis indicated that HuR, KSRP and TIAR bound to one or more loci in the 3'UTR [21].
• In addition to its transcriptional role, FBP and its closely related siblings FBP2 (KSRP) and FBP3 have been reported to bind RNA and participate in various steps of RNA processing, transport or catabolism [22].
• Some of the KH motifs (KHs) of KSRP directly mediate RNA binding, mRNA decay, and interactions with the exosome and poly(A) ribonuclease (PARN) [9].
• Genetic analysis included DNA sequencing of the MECP2, FBP1, and FBP2 genes [5].
• Four different isolates encoded a Xenopus homolog of the human transcription factor, FUSE-binding protein 2 (FBP2) [14].

Analytical, diagnostic and therapeutic context of KHSRP

• Blockage of binding to p75 receptor neutralized nerve-growth-factor-induced cell death, as measured by immunoassays detecting the presence of cytosolic oligonucleosomes and by TUNEL assay to visualize DNA fragmentation [23].
• Methods p75 Neurotrophin receptor and tyrosine kinase B receptor expression was demonstrated by using FACS analysis and immunohistochemistry [24].
• Apoptotic cleavage of LEDGF/p75 was detected by immunoblotting [4].
• We compared the number and progression of enteric nervous system stem cells in the wild-type (WT) and HSCR rat gut using whole-mount immunohistochemistry for p75, culture and isolation of NC stem cells (NCSCs) by flow cytometry [25].
• Few or no p75 positive motoneurons were observed after distal axotomy in animals at the age of postnatal day 1 and postnatal day 7, whereas the injury induced marked neuronal death [26].

References