SwePub
Sök i LIBRIS databas

  Utökad sökning

onr:"swepub:oai:DiVA.org:uu-227248"
 

Sökning: onr:"swepub:oai:DiVA.org:uu-227248" > The 19S Deubiquitin...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00004251naa a2200445 4500
001oai:DiVA.org:uu-227248
003SwePub
008140624s2014 | |||||||||||000 ||eng|
009oai:prod.swepub.kib.ki.se:129000392
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2272482 URI
0247 a https://doi.org/10.1124/mol.113.0913222 DOI
0247 a http://kipublications.ki.se/Default.aspx?queryparsed=id:1290003922 URI
040 a (SwePub)uud (SwePub)ki
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Wang, Xinu Karolinska Institutet4 aut
2451 0a The 19S Deubiquitinase Inhibitor b-AP15 Is Enriched in Cells and Elicits Rapid Commitment to Cell Death
264 c 2014-04-08
264 1b American Society for Pharmacology & Experimental Therapeutics (ASPET),c 2014
338 a print2 rdacarrier
520 a b-AP15 [(3E, 5E)-3,5-bis[(4-nitrophenyl) methylidene]-1-(prop-2enoyl) piperidin-4-one] is a small molecule inhibitor of the ubiquitin specific peptidase (USP) 14/ubiquitin carboxyl-terminal hydrolase (UCH) L5 deubiquitinases of the 19S proteasome that shows antitumor activity in a number of tumor models, including multiple myeloma. b-AP15 contains an alpha,beta-unsaturated carbonyl unit that is likely to react with intracellular nucleophiles such as cysteine thiolates by Michael addition. We found that binding of b-AP15 to USP14 is partially reversible, and that inhibition of proteasome function is reversible in cells. Despite reversible binding, tumor cells are rapidly committed to apoptosis/cell death after exposure to b-AP15. We show that b-AP15 is rapidly taken up from the medium and enriched in cells. Enrichment provides an explanation of the stronger potency of the compound in cellular assays compared with in vitro biochemical assays. Cellular uptake was impaired by 30-minute pretreatment of cells with low concentrations of N-ethylmaleimide (10 mu M), suggesting that enrichment was thiol dependent. We report that in addition to inhibition of deubiquitinases, b-AP15 inhibits the selenoprotein thioredoxin reductase (TrxR). Whereas proteasome inhibition was closely associated with cell death induction, inhibition of TrxR was not. TrxR inhibition is, however, likely to contribute to triggering of oxidative stress observed with b-AP15. Furthermore, we present structure-activity, in vivo pharmacokinetic, and hepatocyte metabolism data for b-AP15. We conclude that the strong enrichment of b-AP15 in cells and a rapid commitment to apoptosis/cell death are factors that likely contribute to the strong antitumor activity of this compound.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmakologi och toxikologi0 (SwePub)301022 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmacology and Toxicology0 (SwePub)301022 hsv//eng
7001 a Stafford, Williamu Karolinska Institutet4 aut
7001 a Mazurkiewicz, Magdalenau Karolinska Institutet4 aut
7001 a Fryknäs, Mårtenu Uppsala universitet,Cancerfarmakologi och beräkningsmedicin4 aut0 (Swepub:uu)mafry516
7001 a Brjnic, Slavica4 aut
7001 a Zhang, Xiaonanu Karolinska Institutet4 aut0 (Swepub:uu)xiazh773
7001 a Gullbo, Joachimu Uppsala universitet,Cancerfarmakologi och beräkningsmedicin4 aut0 (Swepub:uu)joacgull
7001 a Larsson, Rolfu Uppsala universitet,Cancerfarmakologi och beräkningsmedicin4 aut0 (Swepub:uu)rolflars
7001 a Arner, Elias S. J.u Karolinska Institutet4 aut
7001 a D'Arcy, Padraigu Karolinska Institutet4 aut
7001 a Linder, Stigu Karolinska Institutet,Uppsala universitet,Cancerfarmakologi och beräkningsmedicin4 aut
7102 a Karolinska Institutetb Cancerfarmakologi och beräkningsmedicin4 org
7730 t Molecular Pharmacologyd : American Society for Pharmacology & Experimental Therapeutics (ASPET)g 85:6, s. 932-945q 85:6<932-945x 0026-895Xx 1521-0111
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-227248
8564 8u https://doi.org/10.1124/mol.113.091322
8564 8u http://kipublications.ki.se/Default.aspx?queryparsed=id:129000392

Hitta via bibliotek

Till lärosätets databas

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy