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

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.

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STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

Cancers ◽

10.3390/cancers12092459 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2459

Author(s):

Ping-Lian Yang ◽

Lu-Xin Liu ◽

En-Min Li ◽

Li-Yan Xu

Keyword(s):

Receptor Tyrosine Kinase ◽

Feedback Loop ◽

Target Genes ◽

Dominant Negative ◽

Negative Regulator ◽

Biological Processes ◽

Signal Transducer ◽

Transcription 3 ◽

Resistance To Chemotherapy

Chemoradiotherapy is one of the most effective and extensively used strategies for cancer treatment. Signal transducer and activator of transcription 3 (STAT3) regulates vital biological processes, such as cell proliferation and cell growth. It is constitutively activated in various cancers and limits the application of chemoradiotherapy. Accumulating evidence suggests that STAT3 regulates resistance to chemotherapy and radiotherapy and thereby impairs therapeutic efficacy by mediating its feedback loop and several target genes. The alternative splicing product STAT3β is often identified as a dominant-negative regulator, but it enhances sensitivity to chemotherapy and offers a new and challenging approach to reverse therapeutic resistance. We focus here on exploring the role of STAT3 in resistance to receptor tyrosine kinase (RTK) inhibitors and radiotherapy, outlining the potential of targeting STAT3 to overcome chemo(radio)resistance for improving clinical outcomes, and evaluating the importance of STAT3β as a potential therapeutic approach to overcomes chemo(radio)resistance. In this review, we discuss some new insights into the effect of STAT3 and its subtype STAT3β on chemoradiotherapy sensitivity, and we explore how these insights influence clinical treatment and drug development for cancer.

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

Journal of Pediatric Urology ◽

10.1016/j.jpurol.2007.01.047 ◽

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

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Propofol mediates signal transducer and activator of transcription 3 activation and crosstalk with phosphoinositide 3-kinase/AKT

JAK-STAT ◽

10.4161/jkst.29554 ◽

2014 ◽

Vol 3 (2) ◽

pp. e29554 ◽

Cited By ~ 10

Author(s):

Jayant Shravah ◽

Baohua Wang ◽

Marijana Pavlovic ◽

Ujendra Kumar ◽

David DY Chen ◽

...

Keyword(s):

Signal Transducer ◽

Phosphoinositide 3 Kinase ◽

Transcription 3

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

Endocrinology ◽

10.1210/endocr/bqab169 ◽

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.

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

Cancers ◽

10.3390/cancers10090327 ◽

2018 ◽

Vol 10 (9) ◽

pp. 327 ◽

Cited By ~ 39

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.

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A Dominant Negative Egr Inhibitor Blocks Nerve Growth Factor-Induced Neurite Outgrowth by Suppressing c-Jun Activation: Role of an Egr/c-Jun Complex

Journal of Neuroscience ◽

10.1523/jneurosci.22-10-03845.2002 ◽

2002 ◽

Vol 22 (10) ◽

pp. 3845-3854 ◽

Cited By ~ 46

Author(s):

Yechiel Levkovitz ◽

Jay M. Baraban

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Neurite Outgrowth ◽

Dominant Negative ◽

Nerve Growth

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Initiation and maintenance of NGF-stimulated neurite outgrowth requires activation of a phosphoinositide 3-kinase

Journal of Cell Science ◽

10.1242/jcs.109.2.289 ◽

1996 ◽

Vol 109 (2) ◽

pp. 289-300 ◽

Cited By ~ 3

Author(s):

T.R. Jackson ◽

I.J. Blader ◽

L.P. Hammonds-Odie ◽

C.R. Burga ◽

F. Cooke ◽

...

Keyword(s):

Neurite Outgrowth ◽

Pc12 Cells ◽

Specific Inhibitor ◽

Morphological Differentiation ◽

Sympathetic Neuron ◽

Neuronal Morphology ◽

Regulatory Subunit ◽

Membrane Reorganization ◽

Phosphoinositide 3 Kinase

Application of nerve growth factor (NGF) to PC12 cells stimulates a programme of physiological changes leading to the development of a sympathetic neuron like phenotype, one aspect of which is the development of a neuronal morphology characterised by the outgrowth of neuritic processes. We have investigated the role of phosphoinositide 3-kinase in NGF-stimulated morphological differentiation through two approaches: firstly, preincubation with wortmannin, a reputedly specific inhibitor of phosphoinositide kinases, completely inhibited initial morphological responses to NGF, the formation of actin filament rich microspikes and subsequent neurite outgrowth. This correlated with wortmannin inhibition of NGF-stimulated phosphatidylinositol(3,4,5)trisphosphate (PtdInsP3) and phosphatidylinositol(3,4)bisphosphate (PtdIns(3,4)P2) production and with inhibition of NGF-stimulated phosphoinositide 3-kinase activity in anti-phosphotyrosine immunoprecipitates. Secondly, the overexpression of a mutant p85 regulatory subunit of the phosphoinositide 3-kinase, which cannot interact with the catalytic p110 subunit, also substantially inhibited the initiation of NGF-stimulated neurite outgrowth. In addition, we found that wortmannin caused a rapid collapse of more mature neurites formed following several days exposure of PC12 cells to NGF. These results indicate that NGF-stimulated neurite outgrowth requires the activity of a tyrosine kinase regulated PI3-kinase and suggest that the primary product of this enzyme, PtdInsP3, is a necessary second messenger for the cytoskeletal and membrane reorganization events which occur during neuronal differentiation.

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Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3)

Human Reproduction Update ◽

10.1093/humupd/dmn010 ◽

2008 ◽

Vol 14 (4) ◽

pp. 335-344 ◽

Cited By ~ 106

Author(s):

J. S. Fitzgerald ◽

T. G. Poehlmann ◽

E. Schleussner ◽

U. R. Markert

Keyword(s):

Trophoblast Invasion ◽

Intracellular Cytokine ◽

Signal Transducer ◽

Transcription 3

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ESCRT-dependent targeting of plasma membrane localized KCa3.1 to the lysosomes

AJP Cell Physiology ◽

10.1152/ajpcell.00120.2010 ◽

2010 ◽

Vol 299 (5) ◽

pp. C1015-C1027 ◽

Cited By ~ 19

Author(s):

Corina M. Balut ◽

Yajuan Gao ◽

Sandra A. Murray ◽

Patrick H. Thibodeau ◽

Daniel C. Devor

Keyword(s):

Plasma Membrane ◽

Molecular Mechanisms ◽

Close Association ◽

Significant Inhibition ◽

Dominant Negative ◽

Human Embryonic Kidney Cells ◽

Endosomal Sorting ◽

Escrt Machinery ◽

Interfering Rna

The number of intermediate-conductance, Ca2+-activated K+ channels (KCa3.1) present at the plasma membrane is deterministic in any physiological response. However, the mechanisms by which KCa3.1 channels are removed from the plasma membrane and targeted for degradation are poorly understood. Recently, we demonstrated that KCa3.1 is rapidly internalized from the plasma membrane, having a short half-life in both human embryonic kidney cells (HEK293) and human microvascular endothelial cells (HMEC-1). In this study, we investigate the molecular mechanisms controlling the degradation of KCa3.1 heterologously expressed in HEK and HMEC-1 cells. Using immunofluorescence and electron microscopy, as well as quantitative biochemical analysis, we demonstrate that membrane KCa3.1 is targeted to the lysosomes for degradation. Furthermore, we demonstrate that either overexpressing a dominant negative Rab7 or short interfering RNA-mediated knockdown of Rab7 results in a significant inhibition of channel degradation rate. Coimmunoprecipitation confirmed a close association between Rab7 and KCa3.1. On the basis of these findings, we assessed the role of the ESCRT machinery in the degradation of heterologously expressed KCa3.1, including TSG101 [endosomal sorting complex required for transport (ESCRT)-I] and CHMP4 (ESCRT-III) as well as VPS4, a protein involved in the disassembly of the ESCRT machinery. We demonstrate that TSG101 is closely associated with KCa3.1 via coimmunoprecipitation and that a dominant negative TSG101 inhibits KCa3.1 degradation. In addition, both dominant negative CHMP4 and VPS4 significantly decrease the rate of membrane KCa3.1 degradation, compared with wild-type controls. These results are the first to demonstrate that plasma membrane-associated KCa3.1 is targeted for lysosomal degradation via a Rab7 and ESCRT-dependent pathway.

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