Licochalcone A is a potent inhibitor of TEL-Jak2-mediated transformation through the specific inhibition of Stat3 activation

Funakoshi‐Tago, Megumi; Tago, Kenji; Nishizawa, Chiho; Takahashi, Kyoko; Mashino, Tadahiko; Iwata, Susumu; Inoue, Hideo; Sonoda, Yoshiko; Kimura, Tadashi

doi:10.1016/j.bcp.2008.09.012

Cited by 38 publications

(29 citation statements)

References 39 publications

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“…Strikingly we observed the constitutive DNA binding activity of NF-B in BaF3 cells expressing JAK2 L611S, whereas NF-B activation was induced by Epo stimulation in both BaF3/MSCV cells and BaF3/WT cells (data not shown); however, the detailed mechanism of NF-B activation induced by constitutively active JAK2 mutant is still uncertain. Recently we also reported that Stat3 plays a crucial role in the transforming action of TEL (translocation-Ets-leukemia)-JAK2, another type of active mutant of JAK2 (15). When the activation of Stat3 is inhibited, TEL-JAK2 failed to exhibit the transforming activity.…”

Section: Discussionmentioning

confidence: 99%

“…Cells were then centrifuged at 5,000 rpm for 2 min and resuspended in PBS containing 10 g/ml RNase A (Wako, Tokyo, Japan) and 100 g/ml propidium iodide (Sigma-Aldrich). Following 30-min incubation, cell cycle parameters were determined by flow cytometry analysis using FACSCalibur as described previously (15). All data were recorded and analyzed using CellQuest software.…”

Section: Methodsmentioning

confidence: 99%

“…DNA Fragmentation Assay-Genomic DNA was prepared for gel electrophoresis as described previously (15). Electrophoresis was performed on a 1% (w/v) agarose gel in Tris-boric acid buffer.…”

Section: Methodsmentioning

confidence: 99%

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The Acute Lymphoblastic Leukemia-associated JAK2 L611S Mutant Induces Tumorigenesis in Nude Mice

Funakoshi‐Tago

Tago

Sumi

et al. 2009

Journal of Biological Chemistry

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JAK2 plays important roles in the regulation of a variety of cellular processes including cell migration, proliferation, and protection from apoptosis. Recently the L611S point mutation in JAK2 has been identified in a child with acute lymphoblastic leukemia. Here we analyzed the mechanism by which JAK2 exhibits its oncogenicity. In BaF3 murine hematopoietic cells, L611S mutant increased the expression of antiapoptotic proteins including X chromosome-linked inhibitor of apoptosis protein, inhibitor of apoptosis protein, and Bcl-XL. We also showed that JAK2 L611S mutant protects BaF3 cells from cytokine withdrawal-induced apoptotic cell death and leads to cytokine-independent cell growth. Furthermore BaF3 cells expressing JAK2 L611S mutant gained the ability to induce tumorigenesis in nude mice. The L611S mutant also exhibited malignancy, including prompt invasion and spreading into various organs, leading to rapid lethality of the mice. Finally we showed that a specific JAK2 inhibitor, AG490, potently inhibited cytokine-independent cell growth induced by JAK2 L611S mutant via the induction of apoptotic cell death. In addition, treatment with AG490 significantly inhibited the JAK2 L611S mutant-induced tumorigenesis in nude mice. Thus, our results both in vitro and in vivo strongly suggest that L611S mutant of JAK2 harbors potent oncogenic activity, and this probably requires the antiapoptotic signaling pathway.The tyrosine kinase Janus kinase 2 (JAK2) 2 is the essential component of various cytokine signal transductions. Recent studies showed that JAK2 activates the mitogen-activated protein kinase family (ERK, c-Jun NH 2 -terminal kinase (JNK), and p38), Akt, and the signal transducers and activators of transcription (Stat) family in various tissues and is involved in numerous biological functions such as cell growth, cell survival, and differentiation (1, 2). Therefore, it has been reported that the disruption of the regulation of JAK2 activity is associated with hematopoietic disorders and oncogenesis (3-5).JAK2 contains seven regions with significant sequence homology between the kinases, termed Jak homology (JH) domains (1, 2). The JH1 domain is located within the carboxyl terminus of the protein and contains the tyrosine kinase domain. The adjacent JH2 domain shows close homology to the JH1 domain; however, it lacks critical residues required for tyrosine kinase activity. Under normal conditions, this JH2 domain negatively regulates kinase activity. Theoretical models of JAK2 structure suggest that the JH1 and JH2 domains are facing each other and that the activation loop of JAK2 is buried at this interface (6). Upon activation of JAK2, phosphorylation of the activation loop at Tyr 1007/1008 occurs and is believed to prevent this JH1-JH2 interaction and therefore relieve inhibition (7-9).The JAK2 deletion mutant lacking JH2 domain exhibited receptor-independent constitutive activation (8, 9). Furthermore JH2 domain mutations have been demonstrated to be involved in various myeloproliferative diseases (10 -1...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The Acute Lymphoblastic Leukemia-associated JAK2 L611S Mutant Induces Tumorigenesis in Nude Mice

Funakoshi‐Tago

Tago

Sumi

et al. 2009

Journal of Biological Chemistry

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“…It is well known that licochalcones separated from licorice has various activities, such as chemopreventive, 2 antibacterial, 3 antimalarial, 4 antispasmodic activities. 5 anti-inflammatory, 6 vascular, 7 cytotoxic, 8 anti-proliferative, 9 inhibitor of topoisomerase I, 10 and protein tyrosine phosphatase 1B. 11 Although licorice is widely used in medicine, it is still not fully elucidated which components in licorice are responsible for its various activities.…”

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confidence: 99%

First Total Synthesis of Highly Anti-Inflammatory Active Licochalcone D Through Water-Accelerated [3,3]-Sigmatropic Rearrangement

Kim

Jun²

2013

Bulletin of the Korean Chemical Society

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Licochalcones, derived from the dried roots of Glycyrrhiza inflata, have been reported to show various biological activities including antitumor, antiparasitic, antileishmanial, antioxidative, superoxide scavenging, antibacterial, and PTP1B activity. Licochalcone D has an allyl group on ring A instead of ring B, however, most other natural licochalcones possess the group on ring B. Total synthesis of licochalcone D has not been reported even possessing the strongest anti-inflammatory activity. Therefore, the first total synthesis of licochalcone D has been developed by using water-accelerated [3,3]-sigmatropic rearrangement method.

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“…1 They are reported to have various biological activities; antitumor, 2 anti-inflammatory, 3 vascular, 4 cytotoxic, 5 anti-proliferative, 6 inhibitor of topoisomerase I, 7 protein tyrosinase phosphatase 1B 8 etc. Among these, licochalcone E ( Fig.…”

mentioning

confidence: 99%

Highly Efficient Synthesis of Licochalcone E through Water-Accelerated [3,3]-Sigmatropic Rearrangement of Allyl Aryl Ether

Jeon¹,

Kim²,

Kwon³

et al. 2011

Bulletin of the Korean Chemical Society

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Licochalcone A is a potent inhibitor of TEL-Jak2-mediated transformation through the specific inhibition of Stat3 activation

Cited by 38 publications

References 39 publications

The Acute Lymphoblastic Leukemia-associated JAK2 L611S Mutant Induces Tumorigenesis in Nude Mice

The Acute Lymphoblastic Leukemia-associated JAK2 L611S Mutant Induces Tumorigenesis in Nude Mice

First Total Synthesis of Highly Anti-Inflammatory Active Licochalcone D Through Water-Accelerated [3,3]-Sigmatropic Rearrangement

Highly Efficient Synthesis of Licochalcone E through Water-Accelerated [3,3]-Sigmatropic Rearrangement of Allyl Aryl Ether

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