scholarly journals Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas

2011 ◽  
Vol 208 (7) ◽  
pp. 1359-1366 ◽  
Author(s):  
Camilla Pilati ◽  
Mohamed Amessou ◽  
Michel P. Bihl ◽  
Charles Balabaud ◽  
Jeanne Tran Van Nhieu ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Liver Tumors ◽  
Sh2 Domain ◽  
Signal Transducer ◽  
Somatic Signal ◽  
First Time ◽  
Transcription 3 ◽  
Stat3 Mutations ◽  
Hepatocellular Adenomas

Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumors. 60% of these tumors have IL-6 signal transducer (IL6ST; gp130) mutations that activate interleukin 6 (IL-6) signaling. Here, we report that 12% of IHCA subsets lacking IL6ST mutations harbor somatic signal transducer and activator of transcription 3 (STAT3) mutations (6/49). Most of these mutations are amino acid substitutions in the SH2 domain that directs STAT3 dimerization. In contrast to wild-type STAT3, IHCA STAT3 mutants constitutively activated the IL-6 signaling pathway independent of ligand in hepatocellular cells. Indeed, the IHCA STAT3 Y640 mutant homodimerized independent of IL-6 and was hypersensitive to IL-6 stimulation. This was associated with phosphorylation of tyrosine 705, a residue required for IL-6–induced STAT3 activation. Silencing or inhibiting the tyrosine kinases JAK1 or Src, which phosphorylate STAT3, impaired constitutive activity of IHCA STAT3 mutants in hepatocellular cells. Thus, we identified for the first time somatic STAT3 mutations in human tumors, revealing a new mechanism of recurrent STAT3 activation and underscoring the role of the IL-6–STAT3 pathway in benign hepatocellular tumorigenesis.

scholarly journals The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy

2021 ◽  
Vol 22 (2) ◽  
pp. 603
Author(s):  
Manlio Tolomeo ◽  
Antonio Cascio
Keyword(s):  
Tumor Promoter ◽  
Tumor Type ◽  
Signal Transducer ◽  
Suppressor Factor ◽  
Specific Tumor ◽  
Cytokine Stimulation ◽  
Pleiotropic Functions ◽  
Stat3 Mutations ◽  
Potent Tumor

Signal transducer and activator of transcription (STAT) 3 is one of the most complex regulators of transcription. Constitutive activation of STAT3 has been reported in many types of tumors and depends on mechanisms such as hyperactivation of receptors for pro-oncogenic cytokines and growth factors, loss of negative regulation, and excessive cytokine stimulation. In contrast, somatic STAT3 mutations are less frequent in cancer. Several oncogenic targets of STAT3 have been recently identified such as c-myc, c-Jun, PLK-1, Pim1/2, Bcl-2, VEGF, bFGF, and Cten, and inhibitors of STAT3 have been developed for cancer prevention and treatment. However, despite the oncogenic role of STAT3 having been widely demonstrated, an increasing amount of data indicate that STAT3 functions are multifaced and not easy to classify. In fact, the specific cellular role of STAT3 seems to be determined by the integration of multiple signals, by the oncogenic environment, and by the alternative splicing into two distinct isoforms, STAT3α and STAT3β. On the basis of these different conditions, STAT3 can act both as a potent tumor promoter or tumor suppressor factor. This implies that the therapies based on STAT3 modulators should be performed considering the pleiotropic functions of this transcription factor and tailored to the specific tumor type.

The Role of Signal Transducer and Activator of Transcription 3 (Stat3) in Stretch Injury to Bladder Smooth Muscle Cells

2007 ◽  
Vol 3 ◽  
pp. S35
Author(s):  
Sarel Halachmi ◽  
Karen Aitken ◽  
Martha Szybowska ◽  
Nesrin Sabha ◽  
Shariff Dessouki ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Signal Transducer ◽  
Bladder Smooth Muscle ◽  
Stretch Injury ◽  
Transcription 3

Uterine epithelial LIF receptors contribute to implantation chamber formation in blastocyst attachment

Endocrinology ◽  
2021 ◽  
Author(s):  
Yamato Fukui ◽  
Yasushi Hirota ◽  
Tomoko Saito-Fujita ◽  
Shizu Aikawa ◽  
Takehiro Hiraoka ◽  
...  
Keyword(s):  
Hormone Receptor ◽  
Leukemia Inhibitory Factor ◽  
Ovarian Hormones ◽  
Signal Transducer ◽  
Blastocyst Implantation ◽  
Implantation Process ◽  
Uterine Glands ◽  
Transcription 3

Abstract Recent studies have demonstrated that the formation of an implantation chamber composed of a uterine crypt, an implantation-competent blastocyst, and uterine glands is a critical step in blastocyst implantation in mice. Leukemia inhibitory factor (LIF) activates signal transducer and activator of transcription 3 (STAT3) precursors via uterine LIF receptors (LIFRs), allowing successful blastocyst implantation. Our recent study revealed that the role of epithelial STAT3 is different from that of stromal STAT3. However, both are essential for blastocyst attachment, suggesting the different roles of epithelial and stromal LIFR in blastocyst implantation. However, how epithelial and stromal LIFR regulate the blastocyst implantation process remains unclear. To investigate the roles of LIFR in the uterine epithelium and stroma, we generated Lifr-floxed/lactoferrin (Ltf)-iCre (Lifr eKO) and Lifr-floxed/anti-Mullerian hormone receptor type 2 (Amhr2)-Cre (Lifr sKO) mice with deleted epithelial and stromal LIFR, respectively. Surprisingly, fertility and blastocyst implantation in the Lifr sKO mice were normal despite stromal STAT3 inactivation. In contrast, blastocyst attachment failed, and no implantation chambers were formed in the Lifr eKO mice with epithelial inactivation of STAT3. In addition, normal responsiveness to ovarian hormones was observed in the peri-implantation uteri of the Lifr eKO mice. These results indicate that the epithelial LIFR-STAT3 pathway initiates the formation of implantation chambers, leading to complete blastocyst attachment, and that stromal STAT3 regulates blastocyst attachment without stromal LIFR control. Thus, uterine epithelial LIFR is critical to implantation chamber formation and blastocyst attachment.

scholarly journals The Role of Signal Transducer and Activator of Transcription 3 (STAT3) and Its Targeted Inhibition in Hematological Malignancies

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 327 ◽  
Author(s):  
Loukik Arora ◽  
Alan Kumar ◽  
Frank Arfuso ◽  
Wee Chng ◽  
Gautam Sethi
Keyword(s):  
Hematological Malignancies ◽  
Signal Transducer ◽  
Therapeutic Approaches ◽  
Janus Kinases ◽  
Constitutive Activation ◽  
Targeted Inhibition ◽  
Transcription Activators ◽  
Apoptotic Effects ◽  
Transcription 3

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT protein family, can be phosphorylated by receptor-associated Janus kinases (JAKs) in response to stimulation by cytokines and growth factors. It forms homo- or heterodimers that can translocate to the cell nucleus where they act as transcription activators. Constitutive activation of STAT3 has been found to be associated with initiation and progression of various cancers. It can exert proliferative as well as anti-apoptotic effects. This review focuses on the role of STAT3 in pathogenesis i.e., proliferation, differentiation, migration, and apoptosis of hematological malignancies viz. leukemia, lymphoma and myeloma, and briefly highlights the potential therapeutic approaches developed against STAT3 activation pathway.

scholarly journals Structure−Affinity Relationships of Glutamine Mimics Incorporated into Phosphopeptides Targeted to the SH2 Domain of Signal Transducer and Activator of Transcription 3

2009 ◽  
Vol 52 (19) ◽  
pp. 6126-6141 ◽  
Author(s):  
Pijus K. Mandal ◽  
Zhiyong Ren ◽  
Xiaomin Chen ◽  
Chiyi Xiong ◽  
John S. McMurray
Keyword(s):  
Sh2 Domain ◽  
Signal Transducer ◽  
Transcription 3

The role of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in peripheral nerve sheath tumours

2017 ◽  
Vol 70 (6) ◽  
pp. 946-953 ◽  
Author(s):  
Gauri Panse ◽  
Cheuk H Leung ◽  
Davis R Ingram ◽  
Khalida Wani ◽  
Keila E Torres ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Signal Transducer ◽  
Nerve Sheath ◽  
Transcription 3

Phospholipase D1 mediates bFGF-induced Bcl-2 expression leading to neurite outgrowth in H19-7 cells

2011 ◽  
Vol 441 (1) ◽  
pp. 407-416 ◽  
Author(s):  
Sung Nyo Yoon ◽  
Kang Sik Kim ◽  
Ju Hwan Cho ◽  
Weina Ma ◽  
Hye-Jin Choi ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Dominant Negative ◽  
Signal Transducer ◽  
Downstream Effector ◽  
Phospholipase D1 ◽  
Protein Kinase Cα ◽  
Phosphoinositide 3 Kinase ◽  
Interfering Rna ◽  
Transcription 3

The purpose of the present study was to investigate the role of PLD (phospholipase D) in bFGF (basic fibroblast growth factor)-induced Bcl-2 expression and to examine whether overexpressed Bcl-2 influences neurite outgrowth in immortalized hippocampal progenitor cells (H19-7 cells). We found that Bcl-2 expression was maximally induced by bFGF within 24 h, and that this effect was reduced by inhibiting PLD1 expression with PLD1 small interfering RNA or by overexpressing DN (dominant-negative)-PLD1, whereas PLD1 overexpression markedly induced Bcl-2 expression. bFGF treatment activated Ras, Src, PI3K (phosphoinositide 3-kinase), PLCγ (phospholipase Cγ) and PKCα (protein kinase Cα). Among these molecules, Src and PKCα were not required for Bcl-2 expression. PLD activity was decreased by Ras, PI3K or PLCγ inhibitor, suggesting that PLD1 activation occurred through Ras, PI3K or PLCγ. We found that Ras was the most upstream molecule among these proteins, followed by the PI3K/PLCγ pathway, indicating that bFGF-induced PLD activation took place through the Ras/PI3K/PLCγ pathway. Furthermore, PLD1 was required for activation of JNK (c-Jun N-terminal kinase), which led to activation of STAT3 (signal transducer and activator of transcription 3) and finally Bcl-2 expression. When Bcl-2 was overexpressed, neurite outgrowth was stimulated along with induction of neurotrophic factors such as brain-derived neurotrophic factor and neurotrophin 4/5. In conclusion, PLD1 acts as a downstream effector of bFGF/Ras/PI3K/PLCγ signalling and regulates Bcl-2 expression through JNK/STAT3, which leads to neurite outgrowth in H19-7 cells.

Corrigendum to “Novel role of signal transducer and activator of transcription 3 as a progesterone receptor coactivator in breast cancer” [Steroids 76 (2011) 381–392]

Steroids ◽  
2011 ◽  
Vol 76 (12) ◽  
pp. 1407
Author(s):  
Cecilia J. Proietti ◽  
Wendy Béguelin ◽  
María Celeste Díaz Flaqué ◽  
Florencia Cayrol ◽  
Martín A. Rivas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Signal Transducer ◽  
Transcription 3

scholarly journals Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition

2018 ◽  
Vol 115 (12) ◽  
pp. E2801-E2810 ◽  
Author(s):  
Emanuele Giurisato ◽  
Qiuping Xu ◽  
Silvia Lonardi ◽  
Brian Telfer ◽  
Ilaria Russo ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Signal Transducer ◽  
Targeted Interventions ◽  
Proinflammatory Mediators ◽  
Signaling Mechanisms ◽  
Transcriptional Switch ◽  
Macrophage Polarity ◽  
Transcription 3 ◽  
Deficient Mice

Owing to the prevalence of tumor-associated macrophages (TAMs) in cancer and their unique influence upon disease progression and malignancy, macrophage-targeted interventions have attracted notable attention in cancer immunotherapy. However, tractable targets to reduce TAM activities remain very few and far between because the signaling mechanisms underpinning protumor macrophage phenotypes are largely unknown. Here, we have investigated the role of the extracellular-regulated protein kinase 5 (ERK5) as a determinant of macrophage polarity. We report that the growth of carcinoma grafts was halted in myeloid ERK5-deficient mice. Coincidentally, targeting ERK5 in macrophages induced a transcriptional switch in favor of proinflammatory mediators. Further molecular analyses demonstrated that activation of the signal transducer and activator of transcription 3 (STAT3) via Tyr705 phosphorylation was impaired in erk5-deleted TAMs. Our study thus suggests that blocking ERK5 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting STAT3-induced gene expression.

Sign in / Sign up

Export Citation Format

Share Document