Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rpn7 is one of the lid subunits of the 26 S proteasome regulatory particle. The RPN7 gene is known to be essential, but its function remains to be elucidated. To explore the function of Rpn7, we isolated and characterized temperature-sensitive rpn7 mutants. All of the rpn7 mutants obtained accumulated poly-ubiquitinated proteins when grown at the restrictive temperature. The N-end rule substrate (Ub-Arg-beta-galactosidase), the UFD pathway substrate (Ub-Pro-beta-galactosidase), and cell cycle regulators (Pds1 and Clb2) were found to be stabilized in experiments using one of the rpn7 mutants termed rpn7-3 at the restrictive temperature, indicating its defect in the ubiquitin-proteasome pathway. Subsequent analysis of the structure of the 26 S proteasome in rpn7-3 cells suggested that the defect was in the assembly of the 26 S holoenzyme. The most striking characteristic of the proteasome of the rpn7-3 mutant was that a lid subcomplex affinity-purified from the rpn7-3 cells grown at the restrictive temperature contained only 5 of the 8 lid components, a phenomenon that has not been reported in the previously isolated lid mutants. From these results, we concluded that Rpn7 is required for the integrity of the 26 S complex by establishing a correct lid structure.
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PMID:Rpn7 Is required for the structural integrity of the 26 S proteasome of Saccharomyces cerevisiae. 1510 31

Dose-dependent co-expression of enhanced green fluorescent protein (EGFP) and beta-galactosidase (beta-gal) in the cytoplasm of forebrain neurons of two independent mouse lines resulted in growth retardation, weakness, and premature lethality. In primary motor cortex and striatum, apoptosis, glial fibrillary acidic protein proliferation, and cell loss were found. In addition, we observed aggregations of EGFP and beta-gal that colocalized with ubiquitin. GFP is unlikely to be toxic per se, as a third mouse line that expressed twice as much GFP in the cytoplasm of forebrain neurons as the two affected lines was normal. Cytoplasmic aggregations of EGFP and beta-gal occurred in affected and phenotypically normal mice suggesting a storage function rather than being detrimental. We successfully prolonged survival of affected mice with granulocyte colony-stimulating factor (GCSF) and the antibiotic minocycline. These compounds could protect neurons from EGFP and beta-gal-induced dysfunction, as demise of mice started after treatment was discontinued.
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PMID:Neuronal co-expression of EGFP and beta-galactosidase in mice causes neuropathology and premature death. 1547 68

DNA replication is controlled by the stepwise assembly of the pre-replicative complex and the replication apparatus. Loading of the origin recognition complex (ORC) onto the chromatin is a prerequisite for the assembly of the pre-replicative complex. To define the physiological functions of the mammalian ORC, we cloned ORC subunit cDNAs from mouse NIH3T3 cells and found novel variant forms of Orc1, Orc2, and Orc3 each derived from alternative RNA splicing. The variant form of Orc1, Orc1B, lacks 35 amino acid residues in exon 5; the variant of Orc2, Orc2B, lacks 48 amino acid residues in exon 2. In the Orc3 variant, Orc3B, only 1 amino acid residue is deleted in exon 15. Reverse transcription-PCR analysis showed that the full-length Orc1-3 subunits, Orc1A, Orc2A, and Orc3A, as well as Orc2B and Orc3B, were widely expressed in various mouse cell lines and mouse tissues. In contrast, Orc1B was only expressed in the thymus and at an early embryonic stage. Overexpression of these Orc subunits in cultured cells revealed that Orc1A, Orc2A, Orc3A, Orc2B, and Orc3B are localized in the nucleus, whereas Orc1B remains exclusively in the cytoplasm. Moreover, fusion of the 35 amino acids spliced fragment from mOrc1A with beta-galactosidase resulted in its translocation into the nucleus. When Orc1B is expressed transiently, its degradation occurs in a proteasome-independent manner, whereas Orc1A is rapidly degraded by the ubiquitin-proteasome pathway. Taken together, we conclude that mouse Orc1, Orc2, and Orc3 each exist in two alternative-splicing variants and that naturally occurring Orc1B lacks a functional domain that is essential for nuclear translocation and proteasome-dependent degradation.
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PMID:Novel splicing variant of mouse Orc1 is deficient in nuclear translocation and resistant for proteasome-mediated degradation. 1563 81

Our previous work identified E3 ubiquitin ligases, termed UBR1-UBR7, that contain the approximately 70-residue UBR box, a motif important for the targeting of N-end rule substrates. In this pathway, specific N-terminal residues of substrates are recognized as degradation signals by UBR box-containing E3s that include UBR1, UBR2, UBR4, and UBR5. The other E3s of this set, UBR3, UBR6, and UBR7, remained uncharacterized. Here we describe the cloning and analyses of mouse UBR3. The similarities of UBR3 to the UBR1 and UBR2 E3s of the N-end rule pathway include the RING and UBR domains. We show that HR6A and HR6B, the E2 enzymes that bind to UBR1 and UBR2, also interact with UBR3. However, in contrast to UBR1 and UBR2, UBR3 does not recognize N-end rule substrates. We also constructed UBR3-lacking mouse strains. In the 129SvImJ background, UBR3-/- mice died during embryogenesis, whereas the C57BL/6 background UBR3-/- mice exhibited neonatal lethality and suckling impairment that could be partially rescued by litter size reduction. The adult UBR3-/- mice had female-specific behavioral anosmia. Cells of the olfactory pathway were found to express beta-galactosidase (LacZ) that marked the deletion/disruption UBR3- allele. The UBR3-specific LacZ expression was also prominent in cells of the touch, vision, hearing, and taste systems, suggesting a regulatory role of UBR3 in sensory pathways, including olfaction. By analogy with functions of the UBR domain in the N-end rule pathway, we propose that the UBR box of UBR3 may recognize small compounds that modulate the targeting, by this E3, of its currently unknown substrates.
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PMID:Biochemical and genetic studies of UBR3, a ubiquitin ligase with a function in olfactory and other sensory systems. 1746 90

The second step of dolichol-linked oligosaccharide synthesis in the N-linked glycosylation pathway at the endoplasmic reticulum (ER) membrane is catalyzed by an unusual hetero-oligomeric UDP-N-acetylglucosamine transferase that in most eukaryotes is comprised of at least two subunits, Alg13p and Alg14p. Alg13p is the cytosolic and catalytic subunit that is recruited to the ER by the membrane protein Alg14p. We show that in Saccharomyces cerevisiae, cytosolic Alg13p is very short-lived, whereas membrane-associated Alg13 is relatively stable. Cytosolic Alg13p is a target for proteasomal degradation, and the failure to degrade excess Alg13p leads to glycosylation defects. Alg13p degradation does not require ubiquitin but instead, requires a C-terminal domain whose deletion results in Alg13p stability. Conversely, appending this sequence onto normally long-lived beta-galactosidase causes it to undergo rapid degradation, demonstrating that this C-terminal domain represents a novel and autonomous degradation motif. These data lead to the model that proteasomal degradation of excess unassembled Alg13p is an important quality control mechanism that ensures proper protein complex assembly and correct N-linked glycosylation.
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PMID:Alg13p, the catalytic subunit of the endoplasmic reticulum UDP-GlcNAc glycosyltransferase, is a target for proteasomal degradation. 1833 70

TDP-43 is a DNA/RNA-binding protein implicated in multiple steps of transcriptional and post-transcriptional regulation of gene expression. Alteration of this multifunctional protein is associated with a number of neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin positive inclusions. Whereas a pathological link to neurodegenerative disorders has been established, the cellular and physiological functions of TDP-43 remain unknown. In this study, we show that TDP-43 is a nuclear protein with persistent high-level expression during embryonic development and with progressively decreased protein levels during postnatal development. In mice where the TDP-43 gene (Tardbp) was disrupted using a gene trap that carries a beta-galactosidase marker gene, heterozygous (Tardbp(+/-)) mice are fertile and healthy, but intercrosses of Tardbp(+/-) mice yielded no viable homozygotic null (Tardbp(-/-)) mice. Indeed, Tardbp(-/-) embryos die between 3.5 and 8.5 days of development. Tardbp(-/-) blastocysts grown in cell culture display abnormal expansion of their inner cell mass. The pattern of beta-galactosidase staining at E9.5 Tardbp(+/-) embryos is predominantly restricted to the neuroepithelium and remains prominent in neural progenitors at E10.5-12.5. TDP-43 is detected in spinal cord progenitors and in differentiated motor neurons as well as in the dorsal root ganglia at E12.5. Beta-galactosidase staining of tissues from adult Tardbp(+/-) mice shows widespread expression of TDP-43, including prominent levels in various regions of the central nervous system afflicted in neurodegenerative disorders. These results indicate that TDP-43 is developmentally regulated and indispensible for early embryonic development.
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PMID:TDP-43 is a developmentally regulated protein essential for early embryonic development. 2004 Jun 2


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