scholarly journals Activation of Phosphatidylinositol 3-Kinase Signaling Promotes Aberrant Pituitary Growth in a Mouse Model of Thyroid-Stimulating Hormone-Secreting Pituitary Tumors

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3339-3345 ◽  
Author(s):  
Changxue Lu ◽  
Mark C. Willingham ◽  
Fumihiko Furuya ◽  
Sheue-yann Cheng
Keyword(s):  
Cell Proliferation ◽  
Mouse Model ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Specific Inhibitor ◽  
Pituitary Tumors ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

TSH-secreting pituitary tumors (TSHomas) are pituitary tumors that constitutively secrete TSH. Molecular mechanisms underlying this abnormality are largely undefined. We recently created a knock-in mutant mouse harboring a mutation (denoted as PV) in the thyroid hormone receptor-β gene (TRβPV/PV mouse). As these mice age, they spontaneously develop TSHomas. Using this mouse model, we investigated the role of the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway in the pathogenesis of TSHomas. Concurrent with aberrant growth of pituitaries, AKT and its downstream effectors, mammalian target rapamycin and p70S6K, were activated to contribute to increased cell proliferation and pituitary growth. In addition, activation of AKT led to decreased apoptosis by inhibiting proapoptotic activity of Bcl-2-associated death promoter, further contributing to the aberrant cell proliferation. These results suggest an activated PI3K-AKT pathway could underscore tumorigenesis, raising the possibility that this pathway could be a potential therapeutic target in TSHomas. Indeed, TRβPV/PV mice treated with a PI3K-specific inhibitor, LY294002, showed a significant decrease in pituitary growth. The progrowth signaling via AKT-mammalian target rapamycin-p70S6K and cyclin D1/cyclin-dependent kinase were inhibited, and proapoptotic activity of Bcl-2-associated death promoter was increased by LY294002 treatment. Thus, activation of the PI3K-AKT pathway mediates, at least in part, the aberrant pituitary growth, and the intervention of this signaling pathway presents a novel therapeutic opportunity for TSHomas.

scholarly journals Phosphorylation of MNAR Promotes Estrogen Activation of Phosphatidylinositol 3-Kinase

2006 ◽  
Vol 27 (5) ◽  
pp. 1904-1913 ◽  
Author(s):  
James G. Greger ◽  
Natalie Fursov ◽  
Neil Cooch ◽  
Sean McLarney ◽  
Leonard P. Freedman ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Regulatory Subunit ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Mcf7 Cells ◽  
Control Of Gene Expression ◽  
Novel Scaffold ◽  
Phosphatidylinositol 3

ABSTRACT Estrogen actions are mediated by a complex interface of direct control of gene expression (the so-called “genomic action”) and by regulation of cell signaling/phosphorylation cascades, referred to as the “nongenomic,” or extranuclear, action. We have previously described the identification of MNAR (modulator of nongenomic action of estrogen receptor) as a novel scaffold protein that regulates estrogen receptor alpha (ERα) activation of cSrc. In this study, we have investigated the role of MNAR in 17β-estradiol (E2)-induced activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Consistent with our previous results, a direct correlation was established between MNAR expression levels and E2-induced activation of PI3 and Akt kinases. Endogenous MNAR, ERα, cSrc, and p85, the regulatory subunit of PI3 kinase, interacted in MCF7 cells treated with E2. The interaction between p85 and MNAR required activation of cSrc and MNAR phosphorylation on Tyr 920. Consequently, the mutation of this tyrosine to alanine (Y920A) abrogated the interaction between MNAR and p85 and the E2-induced activation of the PI3K/Akt pathway, which was required for the E2-induced protection of MCF7 cells from apoptosis. Nonetheless, the Y920A mutant potentiated the E2-induced activation of the Src/MAPK pathway and MCF7 cell proliferation, as observed with the wild-type MNAR. These results provide new and important insights into the molecular mechanisms of E2-induced regulation of cell proliferation and apoptosis.

l-Thyroxine vs. 3,5,3′-triiodo-l-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase

2009 ◽  
Vol 296 (5) ◽  
pp. C980-C991 ◽  
Author(s):  
Hung-Yun Lin ◽  
Mingzeng Sun ◽  
Heng-Yuan Tang ◽  
Cassie Lin ◽  
Mary K. Luidens ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Hormone Receptor ◽  
Hypoxia Inducible Factor ◽  
Src Kinase ◽  
Rgd Peptide ◽  
Pi3 Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Mitogen Activated Protein ◽  
Phosphatidylinositol 3

3,5,3′-Triiodo-l-thyronine (T3), but not l-thyroxine (T4), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an αvβ3 integrin receptor on human glioblastoma U-87 MG cells. Although both T3 and T4 stimulated extracellular signal-regulated kinase (ERK) 1/2, activated ERK1/2 did not contribute to T3-induced Src kinase or PI3-kinase activation, and an inhibitor of PI3-kinase, LY-294002, did not block activation of ERK1/2 by physiological concentrations of T3 and T4. Thus the PI3-kinase, Src kinase, and ERK1/2 signaling cascades are parallel pathways in T3-treated U-87 MG cells. T3 and T4 both caused proliferation of U-87 MG cells; these effects were blocked by the ERK1/2 inhibitor PD-98059 but not by LY-294002. Small-interfering RNA knockdown of PI3-kinase confirmed that PI3-kinase was not involved in the proliferative action of T3 on U-87 MG cells. PI3-kinase-dependent actions of T3 in these cells included shuttling of nuclear thyroid hormone receptor-α (TRα) from cytoplasm to nucleus and accumulation of hypoxia-inducible factor ( HIF)- 1α mRNA; LY-294002 inhibited these actions. Results of studies involving αvβ3 receptor antagonists tetraiodothyroacetic acid (tetrac) and Arg-Gly-Asp (RGD) peptide, together with mathematical modeling of the kinetics of displacement of radiolabeled T3 from the integrin by unlabeled T3 and by unlabeled T4, are consistent with the presence of two iodothyronine receptor domains on the integrin. A model proposes that one site binds T3 exclusively, activates PI3-kinase via Src kinase, and stimulates TRα trafficking and HIF- 1α gene expression. Tetrac and RGD peptide both inhibit T3 action at this site. The second site binds T4 and T3, and, via this receptor, the iodothyronines stimulate ERK1/2-dependent tumor cell proliferation. T3 action here is inhibited by tetrac alone, but the effect of T4 is blocked by both tetrac and the RGD peptide.

scholarly journals The C-terminal Pentapeptide of Nanog Tryptophan Repeat Domain Interacts with Nac1 and Regulates Stem Cell Proliferation but Not Pluripotency

2009 ◽  
Vol 284 (24) ◽  
pp. 16071-16081 ◽  
Author(s):  
Tianhua Ma ◽  
Zhe Wang ◽  
Yunqian Guo ◽  
Duanqing Pei
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Es Cells ◽  
Embryonic Stem ◽  
Akt Pathway ◽  
Wild Type ◽  
Phosphatidylinositol 3 Kinase ◽  
Stem Cell Proliferation ◽  
Phosphatidylinositol 3

Overexpression of Nanog in mouse embryonic stem (ES) cells has been shown to abrogate the requirement of leukemia inhibitory factor for self-renewal in culture. Little is known about the molecular mechanism of Nanog function. Here we describe the role of the tryptophan repeat (WR) domain, one of the two transactivators at its C terminus, in regulating stem cell proliferation as well as pluripotency. We first created a supertransactivator, W2W3×10, by duplicating repeats W2W3 10 times and discovered that it can functionally substitute for wild type WR at sustaining pluripotency, albeit with a significantly slower cell cycle, phenocopying Nanog(9W) with the C-terminal pentapeptide (WNAAP) of WR deleted. ES cells carrying both W2W3×10 and Nanog(9W) have a longer G1 phase, a shorter S phase in cell cycle distribution and progression analysis, and a lower level of pAkt(Ser473) compared with wild type Nanog, suggesting that both mutants impact the cell cycle machinery via the phosphatidylinositol 3-kinase/Akt pathway. Both mutants remain competent in dimerizing with Nanog but cannot form a complex with Nac1 efficiently, suggesting that WNAAP may be involved in Nac1 binding. By tagging Gal4DBD with WNAAP, we demonstrated that this pentapeptide is sufficient to confer Nac1 binding. Furthermore, we can rescue W2W3×10 by placing WNAAP at the corresponding locations. Finally, we found that Nanog and Nac1 synergistically up-regulate ERas expression and promote the proliferation of ES cells. These results suggest that Nanog interacts with Nac1 through WNAAP to regulate the cell cycle of ES cells via the ERas/phosphatidylinositol 3-kinase/Akt pathway, but not pluripotency, thus decoupling cell cycle control from pluripotency.

scholarly journals Triiodothyronine utilizes phosphatidylinositol 3-kinase pathway to activate anti-apoptotic myeloid cell leukemia-1

2008 ◽  
Vol 41 (3) ◽  
pp. 177-186 ◽  
Author(s):  
Maciej Pietrzak ◽  
Monika Puzianowska-Kuznicka
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Cell Leukemia ◽  
Phosphatidylinositol 3 Kinase ◽  
Hek 293 ◽  
Phosphatidylinositol 3

Triiodothyronine (T3) regulates apoptosis in cells according to their developmental stage, cell type, and pathophysiological state. The molecular mechanisms of this regulation, however, have been largely unknown. In this work, we show that the expression of the myeloid cell leukemia-1 (MCL-1) protein, an anti-apoptotic member of B-cell lymphoma-2 (BCL-2) family, increases in thyroid hormone receptor-expressing human kidney-2 (HK2) cells upon 6-h incubation in 100 nM T3; we also describe the molecular mechanisms leading to this phenomenon. Transcription regulation assays performed in human embryonic kidney (HEK) 293 cells show that 100 nM T3 increases transcription from the MCL-1 promoter twofold in the presence of thyroid hormone receptor β1, but not of its α1 isoform. However, this increase is not a result of direct activation via the thyroid hormone-response element, TRE-DR4, located at the −998 to −983 position in this promoter; furthermore, the presence of 9-cis-retinoic acid receptor is not required. The promoter's activation is abolished in the presence of phosphatidylinositol 3-kinase (PI3-K) inhibitor, wortmannin. The −295 to −107 promoter fragment contains all sequences involved in T3-dependent activation of the MCL-1 promoter, and cAMP-responsive element located at the −262 to −255 position is a major mediator in this process. Therefore, MCL-1 expression is activated by T3, which increases its promoter activity by a non-genomic mechanism using the PI3-K signal transduction pathway. We propose that this is another mechanism by which T3 regulates apoptosis.

scholarly journals c-Src Is Required for Tropomyosin Receptor Kinase C (TrkC)-induced Activation of the Phosphatidylinositol 3-Kinase (PI3K)-AKT Pathway

2007 ◽  
Vol 283 (3) ◽  
pp. 1391-1400 ◽  
Author(s):  
Wook Jin ◽  
Chohee Yun ◽  
Joon Jeong ◽  
Yangho Park ◽  
Hy-De Lee ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Soft Agar ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Neuronal Tissues ◽  
4T1 Cells ◽  
Effector Pathways ◽  
Primary Human Breast ◽  
Phosphatidylinositol 3

TrkC mediates many aspects of growth and development in the central nervous system. TrkC is expressed in a variety of non-neuronal tissues as well as human cancers. TrkC overexpression may drive tumorigenesis, invasion, and metastatic capability in cancer cells. However, relatively little is known about whether TrkC activity is also essential to maintain the malignant properties in human tumors. TrkC expression leads to the constitutive activation of two major effector pathways, namely the Ras-MAP kinase (MAPK) mitogenic pathway and the phosphatidylinositol 3-kinase (PI3K)-AKT pathway mediating cell survival. However, it remains unclear how TrkC activates Ras-Erk1/2 and/or PI3K-Akt cascades. Here we define some aspects of the molecular mechanisms regulating TrkC-dependent Ras-Erk1/2 and PI3K/Akt activation. We show that endogenous TrkC associated with c-Src in human and mouse cancer cells which express TrkC. TrkC-c-Src complexes were also detected in primary human breast cancer tissues. Suppression of c-Src by RNA interference in highly metastatic 4T1 mammary cancer cells, which express endogenous TrkC, resulted in markedly decreased expression of cyclin D1 and suppression of activation of Ras-Erk1/2 and PI3K-Akt. Moreover, inhibition of c-Src expression almost completely blocks colony formation of 4T1 cells in soft agar. Furthermore, in c-Src-deficient SYF cells, TrkC failed to activate the PI3K-Atk pathway, but not the Ras-Erk1/2 pathway. Therefore these data indicate that TrkC induces the PI3K-Akt cascade through the activation of c-Src.

scholarly journals Long Noncoding RNA HOTAIR Promotes Endometrial Carcinoma Cell Proliferation by Binding to PTEN via the Activating Phosphatidylinositol 3-Kinase/Akt Signaling Pathway

2019 ◽  
Vol 39 (23) ◽  
Author(s):  
Xiao-Hui Zhang ◽  
Pin Hu ◽  
Yang-Qin Xie ◽  
Yong-Jun Kang ◽  
Min Li
Keyword(s):  
Cell Proliferation ◽  
Endometrial Carcinoma ◽  
Noncoding Rna ◽  
Akt Pathway ◽  
Akt Signaling Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Direct Binding ◽  
Ec Cells ◽  
Phosphatidylinositol 3

ABSTRACT Accumulating evidence has demonstrated that long noncoding RNAs (lncRNAs) exert essential biological functions in modulating the progression of endometrial carcinoma (EC). HOX transcript antisense intergenetic RNA (HOTAIR) has been widely recognized as a crucial mediator in various tumors, including EC. However, the specific molecular mechanism of HOTAIR in the development of EC remains to be further explored. In the present study, we demonstrated that HOTAIR was significantly upregulated in EC tissues; this was negatively correlated with PTEN but positively correlated with phosphatidylinositol 3-kinase (PI3K) and Akt. Overexpression of HOTAIR promoted proliferation and inhibited apoptosis of EC cells, similar to PTEN knockdown. Additionally, RNA pulldown demonstrated the direct binding relationship between HOTAIR and PTEN. Furthermore, HOTAIR activated the PI3K/Akt pathway to promote EC progression by suppressing PTEN in vivo. Taking these results together, we revealed that high expression of HOTAIR promoted cell proliferation and inhibited apoptosis through activating the PI3K/Akt pathway via binding to PTEN, which might provide a prognostic marker and therapeutic target of EC.

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