Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
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Gene/Protein
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Target Concepts:
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Query: UMLS:C0030567 (
Parkinson's disease
)
63,064
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Inhibitory PAS domain protein
(
IPAS
), a repressor of hypoxia-inducible factor-dependent transcription under hypoxia, was found to exert pro-apoptotic activity in oxidative stress-induced cell death. However, physiological and pathological processes associated with this activity are not known. Here we show that
IPAS
is a key molecule involved in neuronal cell death in
Parkinson's disease
(PD).
IPAS
was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of
IPAS
at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur. Activation of the PINK1-Parkin pathway attenuated
IPAS
-dependent apoptosis.
IPAS
was markedly induced in the midbrain following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, and
IPAS
-deficient mice showed resistance to MPTP-induced degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). A significant increase in
IPAS
expression was found in SNpc neurons in patients with sporadic PD. These results indicate a mechanism of neurodegeneration in PD.
...
PMID:Involvement of inhibitory PAS domain protein in neuronal cell death in Parkinson's disease. 2755 49
Inhibitory PAS domain protein
(
IPAS
) is a bifunctional protein that downregulates hypoxic gene expression and exerts proapoptotic activity by preventing prosurvival activity of Bcl-x
L
and its related factors. Proapoptotic activity of
IPAS
is attenuated by the activation of the PINK1-Parkin pathway, and involved in neuronal degeneration in an experimental mouse model of
Parkinson's disease
. The current study shows that phosphorylation of
IPAS
at Ser184 by MAPK-activated protein kinase 2 (MK2 or MAPKAPK2) enhances the proapoptotic function of
IPAS
. Perinuclear clustering of mitochondria and activation of caspase-3 caused by the transient expression of EGFP-
IPAS
were increased by UVB irradiation. The C-terminal region of
IPAS
mediated the UVB susceptibility of
IPAS
. Increase in
IPAS
-induced mitochondrial clustering by UVB was completly inhibited by the p38 MAPK inhibitor SB203580. Mass spectrometry analysis of UVB-activated
IPAS
identified several phosphorylation sites in the C-terminal region containing p38 MAPK consensus phosphorylation sites at Ser219 and Ser223, and an MK2 consensus site at Ser184. Although mutations of Ser219 and Ser223 to Ala did not suppress the UVB-induced mitochondrial clustering, replacement of Ser184 with Ala blocked it. A phosphomimetic substitution at Ser184 enhanced mitochondrial clustering and activation of caspase-3 without UVB exposure. Furthermore, binding affinity to Bcl-x
L
was increased by the mutation. Treatment of PC12 cells with CoCl
2
caused activation of MK2 and mitochondrial clustering.
IPAS
-dependent cell death induced by CoCl
2
in PC12 cells was decreased by the treatment with the MK2 inhibitor MK2 inhibitor III and by siRNA-directed silencing of MK2.
...
PMID:Increase in proapoptotic activity of inhibitory PAS domain protein via phosphorylation by MK2. 2905 8
