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p(HGNCGENEFAMILY:Proteasome)

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Entity

Name
Proteasome
Namespace
hgnc.genefamily
Namespace Version
20181015
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/3074b85b858455d8eeb76cfcdef685ced19bbe11/external/hgnc.genefamily-names.belns

Appears in Networks 1

Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease v1.0.0

In-Edges 5

a(CHEBI:geldanamycin) increases act(p(HGNCGENEFAMILY:Proteasome)) View Subject | View Object

In CHO cells overexpressing P301L mutant tau, treatment with the Hsp90 inhibitor geldanamycin led to a more pronounced proteasome-mediated reduction in tau phosphorylated at proline-directed S/T sites compared to total tau (67). PubMed:24027553

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a(CHEBI:lactacystin) decreases act(p(HGNCGENEFAMILY:Proteasome)) View Subject | View Object

Additionally, incubation of rat brain extract (containing endogenous tau and proteasomal enzymes) with the proteasome activators Mg2+ and ATP resulted in lower total tau levels with an increase in smaller forms, compared to extract not supplemented with Mg2+ and ATP (73). The loss of tau was blocked by lactacystin giving further evidence that the proteasome was degrading tau (73). PubMed:24027553

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a(HBP:"Tau aggregates") decreases act(p(HGNCGENEFAMILY:Proteasome)) View Subject | View Object

This may suggest that abnormal proteins themselves may interfere with proteasomal degradative processes. Indeed, in vitro aggregated paired helical filament tau could inhibit proteasome activity (69). PubMed:24027553

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complex(p(HGNC:MAPT), p(HGNCGENEFAMILY:Proteasome)) hasComponent p(HGNCGENEFAMILY:Proteasome) View Subject | View Object

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composite(a(CHEBI:"magnesium(2+)"), a(CHEBI:ATP)) increases act(p(HGNCGENEFAMILY:Proteasome)) View Subject | View Object

For example, in the study where rat brain extract was incubated with Mg2+ and ATP, there was an overall decrease in tau due to proteasomal activity; however tau phosphorylated at the PHF1 and Tau-1 epitopes seemed to be preferentially degraded as they were non-detectable within 3 h (73). The preferential degradation of specific phospho-forms of tau by a particular pathway has been reported in other studies as well. PubMed:24027553

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MeSH
Brain
Text Location
Review

Out-Edges 10

act(p(HGNCGENEFAMILY:Proteasome)) increases deg(p(HGNC:MAPT, pmod(Ub))) View Subject | View Object

Not surprisingly, if recombinant tau is incubated with isolated 20S proteasomal complexes, degradation occurs (65). In this system proteolysis is bidirectional. Also, if tau is first ubiquitylated in an in vitro reaction and then incubated with isolated 26S proteasomes supplemented with MgCl2 and ATP, degradation proceeds (66). These data indicate tau can be a substrate for both forms of the proteasome. PubMed:24027553

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p(HGNCGENEFAMILY:Proteasome) increases deg(p(HGNC:MAPT, pmod(Ub))) View Subject | View Object

For example, if HEK cells are transfected with tau and ubiquitin, tau is readily ubiquitylated and degraded by the proteasome (66). PubMed:24027553

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act(p(HGNCGENEFAMILY:Proteasome)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Additionally, incubation of rat brain extract (containing endogenous tau and proteasomal enzymes) with the proteasome activators Mg2+ and ATP resulted in lower total tau levels with an increase in smaller forms, compared to extract not supplemented with Mg2+ and ATP (73). The loss of tau was blocked by lactacystin giving further evidence that the proteasome was degrading tau (73). PubMed:24027553

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p(HGNCGENEFAMILY:Proteasome) increases deg(p(HGNC:MAPT)) View Subject | View Object

This is supported by evidence that full-length tau, which has a lower propensity for aggregating, is cleared by the proteasome while caspase- cleaved tau, which is more aggregate prone, goes through autophagy (72). Also, aggregated tau can be cleared by inducing autophagy (70, 96). PubMed:24027553

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act(p(HGNCGENEFAMILY:Proteasome)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Soluble, monomeric tau is an ideal proteasomal substrate. Indeed, it has been clearly demonstrated that tau can be degraded by the proteasome (65–67, 73). It thus can be suggested that under physiologic circumstances much of tau is degraded in this manner, with select modified forms being cleared by autophagy.However, within the context of the AD milieu, additional tau modifications and degradative impairments may cause the balance to shift away from proteasomal degradation toward autophagy. PubMed:24027553

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act(p(HGNCGENEFAMILY:Proteasome)) increases deg(p(RGD:Mapt)) View Subject | View Object

For example, in the study where rat brain extract was incubated with Mg2+ and ATP, there was an overall decrease in tau due to proteasomal activity; however tau phosphorylated at the PHF1 and Tau-1 epitopes seemed to be preferentially degraded as they were non-detectable within 3 h (73). The preferential degradation of specific phospho-forms of tau by a particular pathway has been reported in other studies as well. PubMed:24027553

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MeSH
Brain
Text Location
Review

act(p(HGNCGENEFAMILY:Proteasome)) increases deg(p(RGD:Mapt, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404))) View Subject | View Object

For example, in the study where rat brain extract was incubated with Mg2+ and ATP, there was an overall decrease in tau due to proteasomal activity; however tau phosphorylated at the PHF1 and Tau-1 epitopes seemed to be preferentially degraded as they were non-detectable within 3 h (73). The preferential degradation of specific phospho-forms of tau by a particular pathway has been reported in other studies as well. PubMed:24027553

Appears in Networks:
Annotations
MeSH
Brain
Text Location
Review

act(p(HGNCGENEFAMILY:Proteasome)) increases deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

In CHO cells overexpressing P301L mutant tau, treatment with the Hsp90 inhibitor geldanamycin led to a more pronounced proteasome-mediated reduction in tau phosphorylated at proline-directed S/T sites compared to total tau (67). PubMed:24027553

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Text Location
Review

act(p(HGNCGENEFAMILY:Proteasome)) causesNoChange deg(a(HBP:"Tau aggregates")) View Subject | View Object

Soluble, monomeric tau is an ideal proteasomal substrate. Indeed, it has been clearly demonstrated that tau can be degraded by the proteasome (65–67, 73). It thus can be suggested that under physiologic circumstances much of tau is degraded in this manner, with select modified forms being cleared by autophagy.However, within the context of the AD milieu, additional tau modifications and degradative impairments may cause the balance to shift away from proteasomal degradation toward autophagy. PubMed:24027553

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MeSH
Alzheimer Disease
Text Location
Review

act(p(HGNCGENEFAMILY:Proteasome)) causesNoChange deg(a(HBP:"Tau oligomers")) View Subject | View Object

For example, as discussed above, certain modified forms of tau, such as caspase-cleaved tau, have a stronger tendency to aggregate. As tau begins to assemble into oligomers, it may become increasingly undesirable as a proteasomal substrate. These low-order, soluble oligomers may be preferentially degraded by autophagy. PubMed:24027553

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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.