Identification of novel regulators of STAT3 activity

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http://hdl.handle.net/10138/316193

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Parri , E , Kuusanmäki , H , van Adrichem , A J , Kaustio , M & Wennerberg , K 2020 , ' Identification of novel regulators of STAT3 activity ' , PLoS One , vol. 15 , no. 3 , 0230819 . https://doi.org/10.1371/journal.pone.0230819

Titel: Identification of novel regulators of STAT3 activity
Författare: Parri, Elina; Kuusanmäki, Heikki; van Adrichem, Arjan J.; Kaustio, Meri; Wennerberg, Krister
Upphovmannens organisation: Institute for Molecular Medicine Finland
University of Helsinki
Datum: 2020-03-31
Språk: eng
Sidantal: 18
Tillhör serie: PLoS One
ISSN: 1932-6203
DOI: https://doi.org/10.1371/journal.pone.0230819
Permanenta länken (URI): http://hdl.handle.net/10138/316193
Abstrakt: STAT3 mediates signalling downstream of cytokine and growth factor receptors where it acts as a transcription factor for its target genes, including oncogenes and cell survival regulating genes. STAT3 has been found to be persistently activated in many types of cancers, primarily through its tyrosine phosphorylation (Y705). Here, we show that constitutive STAT3 activation protects cells from cytotoxic drug responses of several drug classes. To find novel and potentially targetable STAT3 regulators we performed a kinase and phosphatase siRNA screen with cells expressing either a hyperactive STAT3 mutant or IL6-induced wild type STAT3. The screen identified cell division cycle 7-related protein kinase (CDC7), casein kinase 2, alpha 1 (CSNK2), discoidin domain-containing receptor 2 (DDR2), cyclin-dependent kinase 8 (CDK8), phosphatidylinositol 4-kinase 2-alpha (PI4KII), C-terminal Src kinase (CSK) and receptor-type tyrosine-protein phosphatase H (PTPRH) as potential STAT3 regulators. Using small molecule inhibitors targeting these proteins, we confirmed dose and time dependent inhibition of STAT3-mediated transcription, suggesting that inhibition of these kinases may provide strategies for dampening STAT3 activity in cancers.
Subject: 1182 Biochemistry, cell and molecular biology
PROTEIN-TYROSINE-PHOSPHATASE
LYMPHOPROLIFERATIVE DISORDERS
MYCOPLASMA-FERMENTANS
ACTIVATION
KINASE
CANCER
INHIBITION
TRANSCRIPTION
MUTATIONS
SRC
Referentgranskad: Ja
Licens: cc_by
Användningsbegränsning: openAccess
Parallelpublicerad version: publishedVersion


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