Okadaic Acid Induces Hyperphosphorylation of τ Independently of Mitogen‐Activated Protein Kinase Activation

Ho, Duncan T.; Shayan, Hossein; Murphy, Timothy H.

doi:10.1046/j.1471-4159.1997.68010106.x

Cited by 20 publications

(4 citation statements)

References 22 publications

(35 reference statements)

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“…8). To confirm that the increased phosphatase activity directly leads to MG‐mediated tau dephosphorylation (Goedert et al, 1995), cells were pretreated with 250 nM okadaic acid, a selective inhibitor for PP‐2A and PP‐1 but not for PP‐2B and PP‐2C (Ho et al, 1997), followed by the application of 10 μM p BrBzGSCp 2 . Okadaic acid significantly inhibits the p BrBzGSCp 2 ‐induced dephosphorylation after 12 hr (Fig.…”

Section: Resultsmentioning

confidence: 99%

Pathological effects of glyoxalase I inhibition in SH‐SY5Y neuroblastoma cells

Kuhla

Lüth

Haferburg³

et al. 2006

J of Neuroscience Research

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In Alzheimer's disease (AD), in aging, and under conditions of oxidative stress, the levels of reactive carbonyl compounds continuously increase. Accumulating carbonyl levels might be caused by an impaired enzymatic detoxification system. The major dicarbonyl detoxifying system is the glyoxalase system, which removes methylglyoxal in order to minimize cellular impairment. Although a reduced activity of glyoxalase I was evident in aging brains, it is not known how raising the intracellular methylglyoxal level influences neuronal function and the phosphorylation pattern of tau protein, which is known to be abnormally hyperphosphorylated in AD. To simulate a reduced glyoxalase I activity, we applied an inhibitor of glyoxalase I, p-bromobenzylglutathione cyclopentyl diester (pBrBzGSCp(2)), to SH-SY5Y neuroblastoma cells to induce chronically elevated methylglyoxal concentrations. We have shown that 10 microM pBrBzGSCp(2) leads to a fourfold elevation of the methylglyoxal level after 24 hr. In addition, glyoxalase I inhibition leads to reduced cell viability, strongly retracted neuritis, increase in [Ca(2+)](i), and activation of caspase-3. However, pBrBzGSCp(2) did not lead to tau "hyper"-phosphorylation despite activation of p38 mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase but rather activated protein phosphatases 2 and induced tau dephosphorylation at the Ser(202)/Thr(205) and Ser(396)/Ser(404) epitopes. Preincubation with the carbonyl scavenger aminoguanidine prevented tau dephosphorylation, indicating the specific effect of methylglyoxal. Also, pretreatment with the inhibitor okadaic acid prevented tau dephosphorylation, indicating that methylglyoxal activates PP-2A. In summary, our data suggest that a reduced glyoxalase I activity mimics some changes associated with neurodegeneration, such as neurite retraction and apoptotic cell death.

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Section: Resultsmentioning

confidence: 99%

Pathological effects of glyoxalase I inhibition in SH‐SY5Y neuroblastoma cells

Kuhla

Lüth

Haferburg³

et al. 2006

J of Neuroscience Research

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“…Reasoning that the activated kinases could be cycling, the protein phosphatase 1/2a inhibitor, okadaic acid (OA) was added at a concentration that inhibits such enzymes (29). The OA increased the phosphorylated ERK1/2 and p38 signals by at least 10-20 fold, presumably by preventing dephosphorylation within the MAPK pathways and allowing the intermediates to accumulate (30). In the absence of GST-L E , OA had only a modest effect on Nup62 phosphorylation in these reactions, as measured by autoradiography (Fig 1D, OA lane).…”

Section: Resultsmentioning

confidence: 99%

Three cardiovirus Leader proteins equivalently inhibit four different nucleocytoplasmic trafficking pathways

2015

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Cardiovirus infections inhibit nucleocytoplasmic trafficking by Leader protein-induced phosphorylation of Phe/Gly-containing nucleoporins (Nups). Recombinant Leader from encephalomyocarditis virus, Theiler’s murine encephalomyelitis virus and Saffold virus target the same subset of Nups, including Nup62 and Nup98, but not Nup50. Reporter cell lines with fluorescence mCherry markers for M9, RS and classical SV40 import pathways, as well as the Crm1-mediated export pathway, all responded to transfection with the full panel of Leader proteins, showing consequent cessation of path-specific active import/export. For this to happen, the Nups had to be presented in the context of intact nuclear pores and exposed to cytoplasmic extracts. The Leader phosphorylation cascade was not effective against recombinant Nup proteins. The findings support a model of Leader-dependent Nup phosphorylation with the purpose of disrupting Nup-transportin interactions.

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“…Protein kinase B undergoes a 2-to 10-fold activation under OA conditions and is likely to inactivate its physiological substrate, GSK-3␤ [Cross et al, 1995;van Weeren et al, 1998]. Therefore, proline-directed kinases other than GSK-3␤ may play a role in phosphorylating Thr212 of tau but their identity remains to be established [Lovestone et al, 1994;Ho et al, 1997]. Potential candidates are the apoptotic Cdc2-related kinases which are indirectly activated by OA [Liu et al, 1995;Vincent et al, 1997;Tanaka et al, 1998] and other members of the Cdc2 family, including Cdk5 [Patrick et al, 1999].…”

Section: Phosphorylation At Thr212: Gsk-3␤ or Cdc2?mentioning

confidence: 99%

“…OA treatment increases the phosphorylation level of endogenous tau in both primary cell cultures [Arias et al, 1993;Litersky et al, 1996;Ho et al, 1997;Kim et al, 1999] and transformed cell cultures lacking tau transfection [Shea and Fischer, 1996;Bondareff et al, 1998;Xie et al, 1998]. Although this treatment could generate conformationand phosphorylation-sensitive epitopes associated with PHFs, induction of the AT100 epitope has not been reported.…”

Section: Introductionmentioning

confidence: 99%