STAT3-, DNMT1 and NPM1-ALK-dependent ZAP70 gene silencing

Stable Identifier
R-HSA-9851133
Type
Reaction [omitted]
Species
Homo sapiens
Compartment
nucleoplasm, cytosol
ReviewStatus
5/5
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
STAT3-, DNMT1 and NPM1-ALK-dependent ZAP70 gene silencing
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
Expression of ZAP70 and other components of the TCR signaling pathway such as LAT, SLP76 and CD3 are downregulated by NPM1-ALK in a kinase dependent fashion. Repression of ZAP70 depends on STAT3 and DNMT1 and is coincident with increased methylation of 8 CpG islands in the intron 1- exon 2 boundary region (Ambrogio et al, 2009). Although STAT3 is known to induce hypermethylation of target genes by binding and recruiting DNMT1, in the case of ZAP70, neither direct binding of STAT3 to the ZAP70 promoter nor a direct interaction of STAT3 and DNMT1 has been demonstrated (Ambrogio et al, 2009; Zhang et al, 2005; Zhang et al, 2007).
Literature References
PubMed ID Title Journal Year
19887607 NPM-ALK oncogenic tyrosine kinase controls T-cell identity by transcriptional regulation and epigenetic silencing in lymphoma cells

Chiarle, R, di Celle, PF, Ambrogio, C, Tondat, F, Martinengo, C, Inghirami, G, Riera, L, Voena, C

Cancer Res 2009
17922009 STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression

Liu, X, Wasik, MA, Zhang, Q, Wang, HY

Nat. Med. 2007
15870198 STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes

Wasik, MA, Zhang, Q, Wang, HY, Marzec, M, Raghunath, PN, Nagasawa, T

Proc Natl Acad Sci U S A 2005
Participants
Input
Output
Participates
as an event of
This event is regulated
Negatively by
Regulator
p-Y705,S727-STAT3 dimer [nucleoplasm] (Homo sapiens)
Active Unit
p-Y705,S727-STAT3 dimer [nucleoplasm]
Regulator
DNMT1 [nucleoplasm] (Homo sapiens)
Active Unit
DNMT1 [nucleoplasm]
p-Y705,S727-STAT3 dimer [nucleoplasm]
Disease
Name Identifier Synonyms
anaplastic large cell lymphoma DOID:0050744
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Rothfels, K  (2023-10-14)
Reviewed
Turner, S  (2023-11-08)
Created
Rothfels, K  (2023-10-12)
Cite Us!