" Harvinainen
parantumaton sairaus tukki Markku Laitisen valtimot ja vei näön –
lääkärin nerokkaan oivalluksen ansiosta tautiin kehitetään nyt lääkettä
Markku
Laitisen sairastama PXE-sairaus on diagnosoitu Suomessa vain 28
ihmisellä. Tähän ihoon, silmiin ja verisuoniin vaikuttavaan
salakavalasti etenevään sairauteen ei ole olemassa hoitoa. Kunnes
Tampereella Taysissa työskentelevä lääkäri Pasi Nevalainen keksi, että
sairautta voidaan hoitaa elintarvikkeissa lisäaineena käytettävällä
pyrofosfaatilla."
Tässä on tärkeä kartta PXE asiasta.
Muistiin 19.3. 2019
Sitaatti linkistä 2.
"Background
Pseudoxanthoma
elasticum (PXE) is characterized by skin (papular lesions), ocular
(subretinal neovascularisation) and cardiovascular manifestations
(peripheral artery disease), due to mineralization and fragmentation of
elastic fibres in the extracellular matrix (ECM). Caused by mutations in
the ABCC6 gene, the mechanisms underlying this disease remain unknown.
The knowledge on the molecular background of soft tissue mineralization
largely comes from insights in vascular calcification, with involvement
of the osteoinductive Transforming Growth Factor beta (TGFβ) family
(TGFβ1-3 and Bone Morphogenetic Proteins [BMP]), together with
ectonucleotides (ENPP1), Wnt signalling and a variety of local and
systemic calcification inhibitors. In this study, we have investigated
the relevance of the signalling pathways described in vascular soft
tissue mineralization in the PXE knock-out mouse model and in PXE
patients.
Methods
ABC- geeneistäL
ABCC6 (MRP alaperhettä)
https://www.ncbi.nlm.nih.gov/gene/4363
Also known as ARA; PXE; MLP1; MRP6; PXE1; URG7; ABC34; GACI2; MOATE; MOAT-E; EST349056
Summary The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). The encoded protein, a member of the MRP subfamily, is involved in multi-drug resistance. Mutations in this gene cause pseudoxanthoma elasticum. Alternatively spliced transcript variants that encode different proteins have been described for this gene. [provided by RefSeq, Jul 2008] Expression Biased expression in liver (RPKM 16.7), kidney (RPKM 9.5) and 9 other tissues See more Orthologsmouse all
Methods
The
role of the pro-osteogenic pathways
BMP2-SMADs-RUNX2,
TGFβ-SMAD2/3 and
Wnt-MSX2,
apoptosis and ER stress was evaluated using
immunohistochemistry, mRNA expression profiling and immune-co-staining
in dermal tissues and fibroblast cultures of PXE patients and the eyes
and whiskers of the PXE knock-out mouse. Apoptosis was further evaluated
by TUNEL staining and siRNA mediated gene knockdown. ALPL activity in
PXE fibroblasts was studied using ALPL stains.
Results
We
demonstrate the upregulation of the BMP2-SMADs-RUNX2 and TGFβ-2-SMAD2/3
pathway, co-localizing with the mineralization sites, and the
involvement of MSX2-canonical Wnt signalling. Further, we show that
apoptosis is also involved in PXE with activation of Caspases and BCL-2.
In contrast to vascular calcification, neither the other BMPs and TGFβs
nor endoplasmic reticulum stress pathways seem to be perturbed in PXE.
Conclusions
Our
study shows that we cannot simply extrapolate knowledge on cell
signalling in vascular soft tissue calcification to a multisystem
ectopic mineralisation disease as PXE.
Contrary, we demonstrate a
specific set of perturbed signalling pathways in PXE patients and the
knock-out mouse model. Based on our findings and previously reported
data, we propose a preliminary cell model of ECM calcification in PXE. Keywords: Pseudoxanthoma
elasticum, Ectopic mineralization, Elastic fibres, Osteogenic
signalling pathway, BMP2-SMADs-RUNX2, TGFβ signalling, Canonical Wnt
pathway, Apoptosis, Endoplasmic reticulum stress.
ABC- geeneistäL
ABCC6 (MRP alaperhettä)
https://www.ncbi.nlm.nih.gov/gene/4363
Also known as ARA; PXE; MLP1; MRP6; PXE1; URG7; ABC34; GACI2; MOATE; MOAT-E; EST349056
Summary The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). The encoded protein, a member of the MRP subfamily, is involved in multi-drug resistance. Mutations in this gene cause pseudoxanthoma elasticum. Alternatively spliced transcript variants that encode different proteins have been described for this gene. [provided by RefSeq, Jul 2008] Expression Biased expression in liver (RPKM 16.7), kidney (RPKM 9.5) and 9 other tissues See more Orthologsmouse all
- URG: BACKGROUND INFORMATION: Up-regulated Gene clone 7 (URG7) is an ER resident protein, whose expression is up-regulated in the presence of hepatitis B virus X antigen (HBxAg) during HBV infection. In virus-infected hepatocytes, URG7 shows an anti-apoptotic activity due to the PI3K/AKT signalling activation, does not seem to have tumorigenic properties, but it appears to promote the development and progression of fibrosis. However, the molecular mechanisms underlying URG7 activity remain largely unknown. To shed light on URG7 activity, we first analysed its interactome in HepG2 transfected cells: this analysis suggests that URG7 could have a role in affecting protein synthesis, folding and promoting proteins degradation. Moreover, keeping into account its subcellular localisation in the ER and that several viral infections give rise to ER stress, a panel of experiments was performed to evaluate a putative role of URG7 in ER stress. Our main results demonstrate that in ER-stressed cells URG7 is able to modulate the expression of Unfolded Protein Response (UPR) markers towards survival outcomes, up-regulating GRP78 protein and down-regulating the pro-apoptotic protein CHOP. Furthermore, URG7 reduces the ER stress by decreasing the amount of unfolded proteins, by increasing both the total protein ubiquitination and the AKT activation and reducing Caspase 3 activation. CONCLUSIONS: All together these data suggest that URG7 plays a pivotal role as a reliever of ER stress-induced apoptosis. SIGNIFICANCE: This is the first characterisation of URG7 activity under ER stress conditions. The results presented here will help to hypothesise new strategies to counteract the antiapoptotic activity of URG7 in the context of the viral infection.
https://www.genecards.org/cgi-bin/carddisp.pl?gene=ABCC6&keywords=URG7
GeneCards Summary for ABCC6 Gene
ABCC6 (ATP Binding Cassette Subfamily C Member 6) is a Protein Coding gene. Diseases associated with ABCC6 include Pseudoxanthoma Elasticum and Arterial Calcification, Generalized, Of Infancy, 2. Among its related pathways are Regulation of activated PAK-2p34 by proteasome mediated degradation and Photodynamic therapy-induced NFE2L2 (NRF2) survival signaling. Gene Ontology (GO) annotations related to this gene include transporter activity and ATPase-coupled transmembrane transporter activity. An important paralog of this gene is ABCC1.
Linkki lisää: NRF2 kohdegeenit ovat iso joukko ja liittyvät mm UPR järjestelmän.
NRF2 proteiinin omassa funktiossa ja säätelyjärjestelmässä on tärkeä KELCH-proteiini KLHL19 eli Keap1( eräs kelch-propellirakenteinen proteiini) https://www.genecards.org/cgi-bin/carddisp.pl?gene=NFE2L2&keywords=NRF2
- EnzymeRegulation:
-
- Activated by cell derived metabolites including itaconate and fumarate. NF2L2_HUMAN,Q16236
- (Microbial infection) Transcription factor activity on antioxidant target genes is significantly inhibited by SARS coronavirus-2/SARS-COV-2. NF2L2_HUMAN,Q16236
