Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steroid receptor coactivator 3 (SRC-3/p/CIP/AIB1/ACTR/RAC3/TRAM-1) is a member of the p160 family of nuclear receptor coactivators, which includes SRC-1 (NCoA-1) and SRC-2 (TIF2/GRIP1/NCoA2). Previous studies indicate that SRC-3 is required for normal animal growth and is often amplified or overexpressed in many cancers, including breast and prostate cancers. However, the mechanisms of SRC-3-mediated growth regulation remain unclear. In this study, we show that overexpression of SRC-3 stimulates cell growth to increase cell size in prostate cancer cell lines. Furthermore, our results indicate that overexpression of SRC-3 can modulate the AKT signaling pathway in a steroid-independent manner, which results in the activation of AKT/mTOR signaling concomitant with an increase in cell size. In contrast, down-regulation of SRC-3 expression in cells by small interfering RNA decreases cell growth, leading to a smaller cell size. Similarly, in SRC-3 null mutant mice, AKT signaling is down-regulated in normally SRC-3-expressing tissues. Taken together, these results suggest that SRC-3 is an important modulator for mammalian cell growth.
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PMID:Role of the steroid receptor coactivator SRC-3 in cell growth. 1456 19

Tamoxifen is the most widely used selective estrogen receptor modulator for breast cancer in clinical use today. However, tamoxifen agonist action in endometrium remains a major hurdle for tamoxifen therapy. Activation of the nonreceptor tyrosine kinase src promotes tamoxifen agonist action, although the mechanisms remain unclear. To examine these mechanisms, the effect of src kinase on estrogen and tamoxifen signaling in tamoxifen-resistant Ishikawa endometrial adenocarcinoma cells was assessed. A novel connection was identified between src kinase and serine 167 phosphorylation in estrogen receptor (ER)-alpha via activation of AKT kinase. Serine 167 phosphorylation stabilized ER interaction with endogenous ER-dependent promoters. Src kinase exhibited the additional function of potentiating the transcriptional activity of Gal-steroid receptor coactivator 1 (SRC-1) and Gal-cAMP response element binding protein-binding protein in endometrial cancer cells while having no effect on Gal-p300-associated factor and Gal fusions of the other p160 coactivators glucocorticoid-interacting protein 1 (transcriptional intermediary factor 2/nuclear coactivator-2/SRC-2) and amplified in breast cancer 1 (receptor-associated coactivator 3/activator of transcription of nuclear receptor/SRC-3). Src effects on ER phosphorylation and SRC-1 activity both contributed to tamoxifen agonist action on ER-dependent gene expression in Ishikawa cells. Taken together, these data demonstrate that src kinase potentiates tamoxifen agonist action through serine 167-dependent stabilization of ER promoter interaction and through elevation of SRC-1 and cAMP response element binding protein-binding protein coactivation of ER.
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PMID:The Src kinase pathway promotes tamoxifen agonist action in Ishikawa endometrial cells through phosphorylation-dependent stabilization of estrogen receptor (alpha) promoter interaction and elevated steroid receptor coactivator 1 activity. 1552 70

The peroxisome proliferation-activated receptor gamma (PPARgamma) is mainly expressed in the adipose tissue and integrates the control of energy, lipid, and glucose homeostasis. The present study, by means of RT-PCR, Western blot, and immunofluorescence techniques, demonstrates that human sperm express the PPARgamma. The functionality of the receptor was evidenced by 15-deoxy-12,14-prostaglandin J(2) (PGJ2) and rosiglitazone (BRL) PPARgamma-agonists that were tested on capacitation, acrosome reaction, and motility. Both treatments also increase AKT phosphorylations and influence glucose and lipid metabolism in sperm. The specificity of PGJ2 and BRL effects through PPARgamma on human sperm was confirmed by an irreversible PPARgamma antagonist, GW9662. Our findings provide evidence that human sperm express a functional PPARgamma whose activation influences sperm physiology. In conclusion, the presence of PPARgamma in male gamete broadens the field of action of this nuclear receptor, bringing us to look towards sperm as an endocrine mobile unit independent of the systemic regulation.
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PMID:Peroxisome proliferator-activated receptor (PPAR)gamma is expressed by human spermatozoa: its potential role on the sperm physiology. 1697 50

Estrogen receptor alpha (ERalpha) functions as both a transcription factor and a mediator of rapid estrogen signaling. Recent studies have shown a role for ERalpha-interacting membranous and cytosolic proteins in ERalpha action, but our understanding of the role of the microtubule network in the modulation of ERalpha signaling remains unclear. Here we found that endogenous ERalpha associates with microtubules through the microtubule-binding protein hematopoietic PBX-interaction protein (HPIP). Biochemical and RNA-interference studies demonstrated that HPIP influences ERalpha-dependent rapid estrogen signaling by acting as a scaffold protein and recruits Src kinase and the p85 subunit of phosphatidylinositol 3-kinase to a complex with ERalpha, which in turn stimulates AKT and MAPK. We also found that ERalpha interacts with beta-tubulin through HPIP. Destabilization of microtubules activated ERalpha signaling, whereas stabilization of microtubules repressed ERalpha transcriptional activity in a HPIP-dependent manner. These findings revealed a role for HPIP-microtubule complex in regulating 17beta-estradiol-ERalpha responses in mammalian cells and discovered an inherent role of microtubules in the action of nuclear receptor.
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PMID:An inherent role of microtubule network in the action of nuclear receptor. 1704 37

The nuclear receptor corepressor (NCoR) regulates the activities of DNA-binding transcription factors. Recent observations of its distribution in the extranuclear compartment raised the possibility that it could have other cellular functions in addition to transcription repression. We previously showed that phosphatidylinositol 3-kinase (PI3K) signaling is aberrantly activated by a mutant thyroid hormone beta receptor (TRbetaPV, hereafter referred to as PV) via physical interaction with p85alpha, thus contributing to thyroid carcinogenesis in a mouse model of follicular thyroid carcinoma (TRbetaPV/PV mouse). Since NCoR is known to modulate the actions of TRbeta mutants in vivo and in vitro, we asked whether NCoR regulates PV-activated PI3K signaling. Remarkably, we found that NCoR physically interacted with and competed with PV for binding to the C-terminal SH2 (Src homology 2) domain of p85alpha, the regulatory subunit of PI3K. Confocal fluorescence microscopy showed that both NCoR and p85alpha were localized in the nuclear as well as in the cytoplasmic compartments. Overexpression of NCoR in thyroid tumor cells of TRbetaPV/PV mouse reduced PI3K signaling, as indicated by the decrease in the phosphorylation of its immediate downstream effector, p-AKT. Conversely, lowering cellular NCoR by siRNA knockdown in tumor cells led to overactivated p-AKT and increased cell proliferation and motility. Furthermore, NCoR protein levels were significantly lower in thyroid tumor cells than in wild-type thyrocytes, allowing more effective binding of PV to p85alpha to activate PI3K signaling and thus contributing to tumor progression. Taken together, these results indicate that NCoR, via protein-protein interaction, is a novel regulator of PI3K signaling and could serve to modulate thyroid tumor progression.
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PMID:Nuclear receptor corepressor is a novel regulator of phosphatidylinositol 3-kinase signaling. 1760 24

The p160 nuclear receptor co-activators represent a family of molecules, which are recruited by steroid nuclear receptors as well as other transcription factors that are overexpressed in several tumors. We investigated the role of one member of this family on the sensitivity of cells to apoptosis. We observed that overexpression of the RAC3 (receptor-associated co-activator-3) p160 co-activator inhibits hydrogen peroxide-induced cell death in human embryonic kidney 293 (HEK293) cells. The mechanism involves the activation of anti-apoptotic pathways mediated through enhanced nuclear factor kappa B (NF-kappaB) activity, inhibition of caspase-9 activation, diminished apoptotic-inducing factor (AIF) nuclear localization and a change in the activation pattern of several kinases, including an increase in both AKT and p38 kinase activities, and inhibition of ERK2. Moreover, RAC3 has been found associated with a protein complex containing AIF, Hsp90 and dynein, suggesting a role for the co-activator in the cytoplasmatic nuclear transport of these proteins associated with cytoskeleton. These results demonstrate that there are several molecular pathways that could be affected by their overexpression, including those not restricted to steroid regulation or the nuclear action of co-activators, which results in diminished sensitivity to apoptosis. Furthermore, this could represent one mechanism by which co-activators contribute to tumor development.
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PMID:The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action. 1796 10

Insulin regulates development, metabolism, and lifespan via a conserved PI3K/Akt pathway that promotes cytoplasmic sequestration of FoxO transcription factors. The regulation of nuclear FoxO is poorly understood. In the nematode Caenorhabditis elegans, insulin-like signaling functions in larvae to inhibit dauer arrest and acts during adulthood to regulate lifespan. In a screen for genes that modulate C. elegans insulin-like signaling, we identified eak-3, which encodes a novel protein that is specifically expressed in the two endocrine XXX cells. The dauer arrest phenotype of eak-3 mutants is fully suppressed by mutations in daf-16/FoxO, which encodes the major target of C. elegans insulin-like signaling, and daf-12, which encodes a nuclear receptor regulated by steroid hormones known as dafachronic acids. eak-3 mutation does not affect DAF-16/FoxO subcellular localization but enhances expression of the direct DAF-16/FoxO target sod-3 in a daf-16/FoxO- and daf-12-dependent manner. eak-3 mutants have normal lifespans, suggesting that EAK-3 decouples insulin-like regulation of development and longevity. We propose that EAK-3 activity in the XXX cells promotes the synthesis and/or secretion of a hormone that acts in parallel to AKT-1 to inhibit the expression of DAF-16/FoxO target genes. Similar hormonal pathways may regulate FoxO target gene expression in mammals.
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PMID:Caenorhabditis elegans EAK-3 inhibits dauer arrest via nonautonomous regulation of nuclear DAF-16/FoxO activity. 1824 54

Steroid hormones exert profound effects on cell growth, development, differentiation, and homeostasis. Their effects are mediated through specific intracellular steroid receptors that act via multiple mechanisms. Among others, the action mechanism starting upon 17beta-estradiol (E2) binds to its receptors (ER) is considered a paradigmatic example of how steroid hormones function. Ligand-activated ER dimerizes and translocates in the nucleus where it recognizes specific hormone response elements located in or near promoter DNA regions of target genes. Behind the classical genomic mechanism shared with other steroid hormones, E2 also modulates gene expression by a second indirect mechanism that involves the interaction of ER with other transcription factors which, in turn, bind their cognate DNA elements. In this case, ER modulates the activities of transcription factors such as the activator protein (AP)-1, nuclear factor-kappaB (NF-kappaB) and stimulating protein-1 (Sp-1), by stabilizing DNA-protein complexes and/or recruiting co-activators. In addition, E2 binding to ER may also exert rapid actions that start with the activation of a variety of signal transduction pathways (e.g. ERK/MAPK, p38/MAPK, PI3K/AKT, PLC/PKC). The debate about the contribution of different ER-mediated signaling pathways to coordinate the expression of specific sets of genes is still open. This review will focus on the recent knowledge about the mechanism by which ERs regulate the expression of target genes and the emerging field of integration of membrane and nuclear receptor signaling, giving examples of the ways by which the genomic and non-genomic actions of ERs on target genes converge.
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PMID:Estrogen signaling multiple pathways to impact gene transcription. 1836 6

Emerging evidence suggests that nuclear receptor (NR) coregulators have potential to act as master genes and their deregulation can promote oncogenesis. Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1/MNAR) is a novel NR coregulator. Its expression is deregulated in hormone-driven cancers. However, the role of PELP1/MNAR in ovarian cancer progression remains unknown. Analysis of serial analysis of gene expression data suggested deregulation of PELP1/MNAR expression in ovarian tumors. Western analysis of PELP1/MNAR in normal and serous ovarian tumor tissues showed 3- to 4-fold higher PELP1/MNAR expression in serous tumors compared with normal ovarian tissues. To examine the significance of PELP1/MNAR in ovarian cancer progression, we have generated model cells that overexpress PELP1/MNAR and ovarian cancer cells in which PELP1/MNAR expression is down-regulated by stable expression of PELP1/MNAR-specific shRNA. Down-regulation of PELP1/MNAR in cancerous ovarian model cells (OVCAR3) resulted in reduced proliferation, affected the magnitude of c-Src and protein kinase B (AKT) signaling, and reduced tumorigenic potential of ovarian cancer cells in a nude mouse model. PELP1/MNAR overexpression in nontumorigenic immortalized surface epithelial cells (IOSE cells) promoted constitutive activation of c-Src and AKT signaling pathways and promoted anchorage-independent growth. Immunohistochemical studies using human ovarian cancer tissue arrays (n = 123) showed that PELP1/MNAR is 2- to 3-fold overexpressed in 60% of ovarian tumors, and PELP1/MNAR deregulation occurs in all different types of ovarian cancer. Collectively, these results suggest that PELP1/MNAR signaling plays a role in ovarian cancer cell proliferation and survival, and that its expression is deregulated in ovarian carcinomas.
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PMID:Role of PELP1/MNAR signaling in ovarian tumorigenesis. 1855 38

Thyroid hormone (T3) is critical in growth, development, differentiation, and maintenance of metabolic homeostasis. Recent studies suggest that thyroid hormone receptors (TRs) not only mediate the biological activities of T3 via nucleus-initiated transcription, but also could act via nongenomic pathways. The striking phenotype of thyroid cancer exhibited by a knockin mutant mouse that harbors a dominant negative TRbeta mutant (TRbeta(PV/PV) mouse) allows the elucidation of novel oncogenic activity of a TRbeta mutant (PV) via extra-nuclear actions. PV physically interacts with the regulatory p85alpha subunit of phosphatidylinositol 3-kinase (PI3K) to activate the downstream AKT-mammalian target of rapamycin (mTOR) and p70(S6K) and PI3K-integrin-linked kinase-matrix metalloproteinase-2 signaling pathways. The PV-mediated PI3K activation results in increased cell proliferation, motility, migration, and metastasis. Remarkably, a nuclear receptor corepressor (NCoR) was found to regulate the PV-activated PI3K signaling by competing with PV for binding to the C-terminal SH2 domain of p85alpha. Over-expression of NCoR in thyroid tumor cells of TRbeta(PV/PV) mice reduces AKT-mTOR-p70(S6K) signaling. Conversely, lowering cellular NCoR by siRNA knockdown in tumor cells leads to over-activated PI3K-AKT signaling to increase cell proliferation and motility. Furthermore, NCoR protein levels are significantly lower in thyroid tumor cells than in wild type thyrocytes, allowing more effective binding of PV to p85alpha to activate PI3K signaling, thereby contributing to tumor progression. Thus, PV, an apo-TRbeta, could act via direct protein-protein interaction to mediate critical oncogenic actions. These studies also uncovered a novel extra-nuclear role of NCoR in modulating the nongenomic actions of a mutated TRbeta in controlling thyroid carcinogenesis.
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PMID:Nongenomic activation of phosphatidylinositol 3-kinase signaling by thyroid hormone receptors. 1901 61


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